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Expression and functions of adenylyl cyclases in the CNS
Fluids and Barriers of the CNS volume 19, Article number: 23 (2022)
Abstract
Adenylyl cyclases (ADCYs), by generating second messenger cAMP, play important roles in various cellular processes. Their expression, regulation and functions in the CNS, however, remain largely unknown. In this review, we first introduce the classification and structure of ADCYs, followed by a discussion of the regulation of mammalian ADCYs (ADCY1-10). Next, the expression and function of each mammalian ADCY isoform are summarized in a region/cell-specific manner. Furthermore, the effects of GPCR-ADCY signaling on blood–brain barrier (BBB) integrity are reviewed. Last, current challenges and future directions are discussed. We aim to provide a succinct review on ADCYs to foster new research in the future.
Background
One important mechanism that cells use to sense their environment is via receptor-mediated signaling. Specifically, environmental signals, such as chemokines and neurotransmitters, bind to receptors at plasma membrane and activate key intracellular signaling molecules (e.g., second messengers), transferring information from outside to inside. One ubiquitous second messenger in various cell types is cyclic adenosine 3′,5′-monophosphate (cAMP), which can act via either a kinase-dependent manner to induce protein phosphorylation or a kinase-independent manner to induce protein–protein interactions [1]. cAMP plays a pivotal role in a variety of fundamental cellular processes [2], and thus its level needs to be tightly regulated. Adenylyl cyclases (ADCYs) catalyze the production of cAMP from ATP, while phosphodiesterases (PDEs) degrade cAMP to 5′-AMP [3, 4]. This review summarizes the structure, regulation, expression and functions of ADCYs in the CNS.
Classification of ADCYs
ADCYs are grouped into six different classes (class I-VI) based on their structural and domain organizations [5]. Class I is the gamma-proteobacterial type found mainly in gram-negative bacteria, such as Escherichia coli [6, 7]. Class II exists in pathogens that secrete toxin proteins, including Bordetella pertussis and Bacillus anthracis [8]. Class III is the universal or ancestral class of ADCYs found in both bacteria and eukaryotes. Since many of the class III ADCYs have been identified in higher eukaryotes and most thoroughly studied in mammals, they are also known as mammalian ADCYs. Class IV has been identified in Yersinia pestis and in ruminal bacteria Aeromonas hydrophila [5]. Class V and class VI are found in anaerobic bacterium Prevotella ruminicola and nitrogen fixing bacterium Rhizobium etli, respectively [9, 10]. The last two classes of ADCYs have not yet been structurally characterized. In this review, we focus on class III/mammalian ADCYs.
Mammalian ADCYs
Mammalian ADCYs have ten isoforms: nine transmembrane ADCYs (ADCY1-9) and one soluble ADCY (sADCY/ADCY10). All transmembrane ADCYs have a similar structure, but are different in their length and sequence at amino acids 1080–1353 [11] (Table 1). They consist of two discrete membrane-spanning (M1 and M2) domains with each containing six transmembrane alpha-helices, a single N-terminal cytosolic domain, and two cytoplasmic (C1 and C2) domains (Fig. 1). The C1 domain lies between two transmembrane domains, while the C2 domain is at the large C-terminus of the protein. These C1/C2 domains are subdivided into C1a/C2a and C1b/C2b subdomains (Fig. 1). The C1a and C2a subdomains are the catalytic site and highly conserved: they are structurally identical and homologous among all 9 transmembrane isoforms, while the C1b and C2b subdomains are the regulatory site [11, 12]. Unlike ADCY1-9, ADCY10 does not have clearly defined transmembrane domains (Table 1) [13]. Its catalytic domain is more related to bicarbonate-sensing ADCY from cyanobacteria than that of ADCY1-9.
Genetic studies have shown that ADCY genes are not clustered in the genome: each isoform is coded by a gene localized on a different chromosome [14, 15] (Table 1). This enables isoform-specific regulation of ADCYs.
Regulation of ADCYs
ADCY activity is mainly regulated by G protein-coupled receptors (GPCRs). G protein is a heterotrimer containing α, β and γ subunits. Based on its function, Gα subunit is divided into four major categories: Gαs, Gαi/o, Gαq/11 and Gα12/13 (Fig. 2). Currently, there are five β and 11 γ subunits, which through forming highly active βγ heterodimers participate in the regulation of various biological processes [16]. Upon ligand binding, GPCRs change their confirmation replace GDP with GTP on Gα subunit, leading to dissociation of Gβγ complex. Then Gα and Gβγ independently activate downstream signaling cascades. The system returns to the resting state when ligands are released from GPCRs, which causes hydrolysis of GTP to GDP on Gα subunit and subsequent reassociation of Gβγ with Gα to form heterotrimers.
Schematic illustration of GPCR-ADCY signaling pathways. Upon ligand binding to the GPCR, GDP on Gα subunit is replaced with GTP, triggering the dissociation of Gβγ from Gα. The dissociated Gα and Gβγ subunits interact with different effectors and signaling molecules. Gαs directly activates ADCY activity, converting ATP to cAMP, which activates PKA and EPAC. Gαi/o directly activates or inhibits ADCY activity depending on ADCY isoforms. In addition, Gαi/o can inhibit the stimulation of Gαs and Ca2+; and activate MAPK pathway and PLC. Gαq/11 indirectly participates in the regulation of ADCY via Ca2+ and PKC, which are generated via PLC-DAG/IP3 signaling pathway. PKC and Ca2+ can either activate or inhibit ADCY activity in an isoform-specific manner. Gα12/13 activates GEFs-RhoA signaling and does not seem to regulate ADCY activity. Gβγ activates or inhibits ADCY activity depending on its Gα partner and ADCY isoforms. Created with BioRender.com
The effect of GPCRs on ADCY activity is dependent on the type of G protein (Fig. 2). Specifically, Gαs directly activates ADCYs, increasing cAMP production. Gαi/o directly activate or inhibit ADCY activity in an ADCY isoform-specific manner. Gαq/11 indirectly regulates ADCY activity via protein kinase C (PKC) and/or Ca2+, which can activate or inhibit ADCY activity. Gα12/13 does not seem to be involved in the regulation of ADCY activity. The dissociated Gβγ complex can either activate or inhibit ADCY activity depending on its Gα partner and ADCY isoforms. It should be noted that Gβγ can also be generated via modulatory protein GoLoco without activation of GPCRs. Similarly, Gβγ generated this way may have stimulatory or inhibitory effect on ADCY activity.
Based on their signaling properties, transmembrane ADCYs are further divided into four groups (Group I-IV). Group I is composed of ADCY1, ADCY3 and ADCY8; Group II includes ADCY2, ADCY4 and ADCY7; Group III consists of ADCY5 and ADCY6; and Group IV contains ADCY9 only. The unique features of these four groups of transmembrane ADCYs and soluble ADCY are discussed below and summarized in Fig. 3.
Group I
Group I ADCYs are activated by Gαs and Ca2+/calmodulin, and inhibited by Gαi/o and Gβγ. It should be noted that these ADCYs have different sensitivity to the stimuli. For example, ADCY3 and ADCY8 are five-fold less sensitive to Ca2+ than ADCY1 [17]. In addition, the activity of group I ADCYs can also be regulated by phosphorylation. For instance, PKCα activates ADCY1 and ADCY3; whereas calcium/calmodulin-dependent protein kinase IV (CaMKIV) inactivates ADCY1, CaMKII and regulator of G protein signaling 2 (RGS2) inactivate ADCY3, and PKA inactivates ADCY8 [18].
Group II
Group II ADCYs are activated by both Gαs and Gβγ with a higher potency on Gαs, but insensitive to Ca2+/calmodulin. Although group II ADCYs are not inhibited by Gαi/o, it is assumed that Gβγ released from Gαi/o stimulation can synergistically stimulate them [11, 15, 19]. In addition, PKC regulates group II ADCYs in an isoform-specific manner. Specifically, PKCα activates ADCY2 but inactivates ADCY4, and PKCδ activates ADCY7 [18].
Group III
Group III ADCYs are activated by Gαs and Gβγ, but inhibited by Gαi/o and free Ca2+. Although most ADCYs are inhibited by high (non-physiological) concentration of Ca2+, ADCY5 and ADCY6 are inhibited by Ca2+ at sub-micromolar level [17], which may have important physiological implications. In addition, ADCY5 is also activated by PKCα/δ and inhibited by RGS2, PKA and Rica8; whereas ADCY6 is inhibited by RGS2, PKA and PKCδ/ε [18].
Group IV
Group IV ADCY is activated solely by Gαs. Unlike other transmembrane ADCYs, ADCY9 is insensitive to forskolin due to the lack of a key leucine residue in the catalytic cleft [20, 21]. Although ADCY9 is not regulated by Gαi/o or Gβγ, calcineurin and PKC are able to inhibit its activity [18].
sADCY/ADCY10
Unlike transmembrane ADCYs, ADCY10 is not associated with the membrane: it is diffusely distributed in the cytoplasm and nucleus [22]. Although ADCY10 is not regulated by G protein and insensitive to forskolin, it is activated by Ca2+ and bicarbonates [22, 23]. The negative regulators of ADCY10 have yet to be identified and the functions of ADCY10 remain largely unknown. It has been reported that nuclear ADCY10 is involved in gene regulation [24], while mitochondrial ADCY10 moderates oxidative phosphorylation in response to CO2/HCO3− generated by citric acid cycle [25, 26].
Expression and functions of ADCYs in the CNS
ADCYs are found in almost all cells and different cell types express distinct ADCY isoforms. The expression patterns of ADCY isoforms are mainly obtained from RNA-sequencing analyses (at the mRNA level). Currently, ADCY expression profiles at the protein level are limited, possibly due to the lack of isoform-specific antibodies.
ADCYs play a variety of important functions in the CNS, ranging from learning/memory to movements. Abnormal ADCY expression is found in and associated with many neurological disorders, including Alzheimer’s disease and depressive disorders. For example, loss of ADCY1 leads to impaired synaptic plasticity and deficits in spatial learning [27], while overexpression of ADCY1 in the forebrain enhances recognition and memory [28]. ADCY8 exerts similar functions as ADCY1 [29,30,31,32,33,34,35] and is associated with bipolar disorder [36] and post-traumatic stress disorder [37] in humans. ADCY3 is involved in olfactory-dependent learning and associated with major depressive disorder in humans [38, 39]. Loss of ADCY5 results in Parkinson-like motor dysfunction and locomotor impairment [40]. ADCY7 is linked to familial major depression in both mice and humans [41, 42]. It should be noted that not all ADCYs are well studied. The functions of ADCY2, ADCY4, ADCY6, ADCY9 and ADCY10 in the CNS remain largely unknown. Here, we discuss and summarize the expression (Table 2) and function (Table 3) of each ADCY isoform in the CNS.
ADCY1
Expression
ADCY1 mRNA is transiently expressed in trigeminal nerve nuclei, striatum, dorsal thalamus, hippocampal interneurons, retinal ganglion cells and cerebellar Purkinje cells in early postnatal life [43]. In adulthood, however, its expression is confined to olfactory bulb, pineal gland, cortex, dentate gyrus, various thalamic nuclei, CA1 region of hippocampus and granule cells of the cerebellum [43, 44]. Bulk RNA-sequencing analysis showed that ADCY1 expression was high in neurons and moderate in oligodendrocytes, microglia and astrocytes [45]. Single-cell RNA-sequencing study demonstrated high and low levels of ADCY1 in vascular fibroblast-like cells and endothelial cells, respectively [46].
Function
As a Ca2+/calmodulin-sensitive ADCY, ADCY1 exerts important functions in neuronal development, a process that is critically regulated by calcium [47]. Correlation studies showed that hippocampal expression of ADCY1 was reduced during aging and increased during the acquisition of spatial learning [48, 49], highlighting a possible role of ADCY1 in learning/memory. In addition, ADCY1-null mice exhibited reduced long-term potentiation (LTP) in hippocampal mossy fibers, impaired cerebellar LTP, and higher threshold to inflammatory and chronic pain [50,51,52]. Consistent with these findings, overexpression of ADCY1 in forebrain led to elevated LTP, improved memory and decreased social ability via increased extracellular signal-related kinase (ERK1/2) [28]. These results suggest that ADCY1 regulates learning/memory, LTP and nociception.
Interestingly, FMR1-null mice, a rodent model of fragile X syndrome, exhibited increased ADCY1 expression and ADCY1-overexpression-like phenotype, including enhanced autism-related behaviors and increased ERK1/2 activity [53]. Loss of ADCY1 in FMR1-null background, however, reversed these changes [53]. These findings suggest that FMR1 inhibits ADCY1 expression, and that loss of FMR1-dependent suppression of ADCY1 is a cause for eccentric neuronal signaling in fragile X syndrome.
In humans, it has been reported that a nonsense mutation in ADCY1 gene causes hearing impairment, deafness and loss of hair cell function [54, 55]. In addition, genome wide analysis studies (GWAS) showed that ADCY1 polymorphism was associated with sleep deprivation, schizophrenia and bipolar disorder [56, 57].
ADCY2
Expression
ADCY2 mRNA is highly expressed in piriform cortex, hippocampus, dentate gyrus, striatum and thalamus [58]. Bulk RNA-sequencing study found that ADCY2 was mainly expressed in astrocytes, neurons and oligodendrocytes precursor cells (OPCs); and to a lesser extent in oligodendrocytes and microglia [45]. Single-cell RNA-sequencing analysis showed that ADCY2 was expressed at high levels in astrocytes, vascular fibroblast-like cells and smooth muscle cells, and at low levels in endothelial cells and pericytes [46]. At the protein level, ADCY2 expression has been found in mouse hippocampus [59], indicating a possible role in synaptic plasticity.
Function
The function of ADCY2 remains largely unknown. A correlation study found that ADCY2 was down-regulated throughout the hippocampus during the acquisition of spatial learning in mice [49], suggesting that ADCY2 may be involved in spatial learning and memory. In addition, it has been reported that P19 cells (embryonic carcinoma cells) up-regulate ADCY2 during neuronal [60] and mesodermal [61] differentiation, highlighting a possible role of ADCY2 in cell differentiation during development.
A recent GWAS study revealed that ADCY2 polymorphism was associated with neuropsychiatric disorders, including bipolar disorder [62, 63], anxiety and stress-like disorders [64], Lesch-Nyhan disease and schizophrenia [65, 66].
ADCY3
Expression
ADCY3 mRNA is highly expressed in olfactory sensory neurons (OSN), neuronal primary cilia, and dorsal root ganglion [67, 68]. Bulk and single-cell RNA-sequencing studies showed that ADCY3 was highly expressed in neurons, OPCs, astrocytes, pericytes and vascular fibroblast-like cells; and moderately expressed in oligodendrocytes, microglia, endothelial cells and smooth muscle cells [45, 46]. At the protein level, ADCY3 is mainly found in primary cilia on choroid plexus cells and astrocytes [69].
Function
The high expression of ADCY3 in olfactory sensory neurons suggests that it may regulate odor/pheromone detection [67, 68]. Consistent with these results, ablation of ADCY3 leads to defective olfactory sensory neuron maturation and abnormal olfactory-based behavioral responses, including lack of preference for the test odorants in both sand-buried food task and odor-associated passive avoidance learning paradigm, absence of inter-male aggressiveness and male sexual behavior, and defective maternal behaviors [19, 70,71,72]. In addition, ADCY3-null mice also exhibit impaired learning/memory and short-term memory loss [38], highlighting an essential role of ADCY3 in learning/memory. Furthermore, dysregulation of ADCY3-mediated cAMP signaling in choroid plexus epithelial cells has also been suggested to contribute to the onset of hydrocephalus [73].
GWAS studies demonstrated that ADCY3 polymorphism was associated with obesity [74,75,76], depression [77], and inflammatory bowel disease [78, 79].
ADCY4
Expression
ADCY4 mRNA is expressed at extremely low levels in various brain regions, including olfactory bulbs, cerebral cortex, hippocampus, amygdala, basal ganglia, thalamus, hypothalamus, pons, medulla and cerebellum [58, 80]. Bulk and single-cell RNA-sequencing analyses demonstrated that ADCY4 expression was predominantly detected in endothelial cells [45, 46]. One study reported ADCY4 expression in dentate gyrus and hippocampal CA1/CA3 regions at the protein level [59].
Function
The expression of ADCY4 in hippocampus and dentate gyrus suggests a possible role in synaptic plasticity [59]. Although ADCY4 is also detected in olfactory cilia [19], it does not seem to play a role in olfactory perception since it cannot rescue anosmia in ADCY3-null mice [19].
Outside the CNS, ADCY4 is mainly expressed in the kidney. However, loss of ADCY4 in kidney collecting duct principal cells fails to affect vasopressin-stimulated cAMP generation or sodium/water reabsorption [81], highlighting a dispensable role of ADCY4 in these cells.
ADCY5
Expression
ADCY5 mRNA is highly expressed in the olfactory system, piriform cortex and striatum; and weakly expressed in thalamus and hippocampus [58, 80]. Bulk and single-cell RNA-sequencing analyses revealed high levels of ADCY5 in neurons, vascular fibroblast-like cells, smooth muscle cells, OPCs and oligodendrocytes; and low levels of ADCY5 in microglia, astrocytes, pericytes and endothelial cells [45, 46]. Consistent with these findings, ADCY5 mRNA is detected in cholinergic interneurons and GABAergic medium spiny neurons in the striatum [82, 83].
Function
In vitro study showed that P19 cells up-regulated ADCY5 during neuronal differentiation [60], highlighting an important role of ADCY5 in neuronal maturation/function. Echoed with this result, knockdown of ADCY5 in nucleus accumbens decreases cAMP, leading to blood–brain barrier (BBB) disruption, social stress and depression-like behaviors [84]. Similarly, ADCY5-null mice exhibit poor stress-coping responses [85], indicating a critical role of ADCY5 in the regulation of anxiety and stress. In addition, loss of ADCY5 also impairs striatum-dependent learning, corticostriatal plasticity, dopamine signaling and motor activity [83, 86].
Outside the CNS, ADCY5 participates in the regulation of heart function. In vitro study showed that ADCY5 expression correlated with the appearance of beating cardiomyocytes and transcription of MLC1A (myosin light chain 1 atrial isoform) during mesodermal differentiation of P19 cells, highlighting an important role of ADCY5 in early cardiogenesis and cardiomyocyte differentiation [61]. In addition, deletion of ADCY5 improves basal left ventricular function [87, 88], protects the heart against chronic βAR stimulation [89] and age-related cardiomyopathy [90, 91]. These results indicate a detrimental role of ADCY5 in heart function.
ADCY5 polymorphism has been linked to neuropsychiatric disorders. For example, a missense mutation (A726T) has been associated with familial dyskinesia with facial myokymia (FDFM) [92]. In addition, a homozygous missense or heterozygous de novo mutation (p.R418W) results in early onset of motor disability and movement disorder with severe intellectual disability [93,94,95].
ADCY6
Expression
ADCY6 has a similar but broader and higher expression pattern as ADCY5. In addition to the olfactory system, piriform cortex and striatum, ADCY6 mRNA is also highly expressed in the limbic areas, including amygdala, hippocampus, dentate gyrus and hypothalamus [58, 80]. Bulk and single-cell RNA-sequencing analyses showed that ADCY6 was highly expressed in neurons, OPCs, oligodendrocytes, astrocytes, endothelial cells, pericytes and smooth muscle cells [45, 46].
Function
The function of ADCY6 in the CNS remains unknown. Outside the CNS, ADCY6 is involved in the pathogenesis of cardiac and renal disorders. In vitro study showed that P19 cells up-regulated ADCY6 during mesodermal differentiation [61]. Expression of ADCY6 in the left ventricle of pigs with congestive heart failure increases cardiac contractility and ameliorates cardiac failure [96]. Although loss of ADCY6 does not affect basal cAMP level, it greatly reduces βAR-stimulated cAMP production [97, 98]. ADCY6-null mice display increased urine output, decreased urine osmolarity, reduced responsiveness to arginine vasopressin (AVP), and mild Bartter syndrome-like phenotype [99]. Together, these findings highlight important roles of ADCY6 in cardiac and renal functions. In addition, homozygous missense mutation (R1116C) in ADCY6 reduces myelination in peripheral nervous system, contributing to human axoglial diseases [100] and lethal congenital contracture syndrome [101]. ADCY6 has also been identified as a prognostic factor involved in DNA methylation-regulated immune processes in luminal-like breast cancer [102].
ADCY7
Expression
ADCY7 mRNA expression is restricted to thalamus and hypothalamus, with lower expression in cerebral cortex, amygdala, corpus callosum, cerebellum and olfactory bulbs [41, 58, 80]. Bulk and single-cell RNA-sequencing analyses showed that ADCY7 was highly expressed in microglia and vascular fibroblast-like cells [45, 46]. At the protein level, ADCY7 expression is mainly found in hippocampus, cerebellum, caudate-putamen, cerebral cortex and nucleus accumbens [103].
Function
Ethanol-induced GABAergic transmission in central amygdala neurons was ablated in ADCY7+/ brain slices [104], while mutant mice overexpressing human ADCY7 in the brain displayed higher plasma adrenocorticotropin and corticosterone levels after ethanol injection [105]. These findings suggest that ADCY7 plays an important role in ethanol modulation of presynaptic GABA release, which may underlie ethanol-related behaviors such as anxiety and dependence.
There is also evidence suggesting that ADCY7 is involved in mood regulation and major depressive disorder. It has been reported that overexpression of ADCY7 in female mice increases depression-like behaviors, while ADCY7+/− mice display decreased depression-like symptoms [42]. Consistent with this finding, a tetranucleotide repeat [(AACA)7] polymorphism in ADCY7 is associated with depressive disorders in humans [42, 65]. Postmortem study found increased ADCY7 expression in the amygdala and anterior cingulate cortex of patients with depression [41].
In addition, ADCY7 is a major contributor of cAMP in T and B lymphocytes. Loss of ADCY7 leads to fewer leukocytes and higher mortality upon bacterial infections [106, 107], indicating an essential role of ADCY7 in immune responses. Consistent with these results, ADCY7 polymorphism is associated with inflammatory bowel disease, Crohn’s disease, ulcerative colitis and autoimmune diseases [108, 109].
ADCY8
Expression
During early postnatal life, ADCY8 mRNA is expressed in hippocampal CA1 region, cortex, cerebellum, olfactory bulb, hypothalamus, amygdala and basal ganglia. In adulthood, ADCY8 is found in olfactory bulb, cerebellum, hypothalamus, thalamus, hippocampal CA1 region, habenula, cerebral and piriform cortices [43, 110]. Bulk and single-cell RNA-sequencing analyses showed that ADCY8 was predominantly expressed in neurons, OPCs and astrocytes [45, 46].
Function
In vitro study showed that P19 cells up-regulated ADCY8 during neuronal differentiation [60], suggesting a possible role of ADCY8 in neuronal development. In vivo study demonstrated that knockdown of ADCY8 ablated the midline-crossing of retinal neurons in zebrafish, resulting in mis-projections of exons to the ipsilateral tectum [111], highlighting an essential role of ADCY8 in axonal pathfinding. ADCY8-null mice showed defective short-term plasticity, impaired presynaptic/postsynaptic LTP and abnormal anxiety-like behaviors under stress [29, 33, 51]. In addition, ADCY8-null mice exhibited no reduction in allodynia and slightly reduced behavioral nociceptive responses to subcutaneous formalin injection or nerve injury [52]. ADCY1-null and ADCY1/ADCY8 double knockout mice, on the other hand, displayed more dramatic changes in these tests [52]. These findings indicate a relatively less important role of ADCY8 in behavioral responses to inflammation or nerve injury compared to ADCY1.
GWAS studies showed that ADCY8 polymorphism was associated with various neuropsychiatric disorders, including dissociative amnesia, post-traumatic stress disorder, depression and bipolar disorder [37, 112, 113].
ADCY9
Expression
ADCY9 mRNA is broadly expressed in the brain with high levels in olfactory system, neocortex, piriform cortex, hippocampus, dentate gyrus, thalamus, hypothalamus and cerebellum [114, 115] Bulk and single-cell RNA-sequencing analyses showed that ADCY9 was highly expressed in almost all cell types in the CNS, including neurons, OPC, oligodendrocytes, astrocytes, microglia, endothelial cells, pericytes, smooth muscle cells and vascular fibroblast-like cells [45, 46].
Function
Although ADCY9 is abundantly expressed in the brain, its function in the CNS remains largely unknown. Loss of ADCY9 leads to grade 1 ventricular diastolic dysfunction and embryonic lethality [116], preventing investigation of its function in adulthood. A study found reduced expression of ADCY9 in the hippocampus in aged mice [48]. More importantly, ADCY9 was significantly increased in mouse hippocampus after spatial learning and its expression correlated with animal performance in the Morris water maze test [48]. These findings suggest that ADCY9 may regulate cognitive function and learning/memory.
In addition, there is also evidence showing that ADCY9 modulates immune function. For example, it has been reported that ADCY9 regulates the chemotaxis of neutrophils and monocytes [117] as well as T cell function [11, 118].
GWAS studies found that ADCY9 polymorphism was associated with asthma [119, 120], mood disorders [121], and the efficacy of dalcetrapib, an antiatherogenic drug [122].
ADCY10
Expression
Bulk RNA-sequencings analysis showed minimal expression of ADCY10 in neurons, OPCs, oligodendrocytes, astrocytes, microglia and endothelial cells [45]. Single-cell RNA-sequencing study found relatively high expression of ADCY10 in endothelial cells and astrocytes [46]. At the protein level, ADCY10 is found in astrocytes [123], developing neurons [124], and neurons of visual cortex, hippocampus and cerebellum [125, 126]. In addition, ADCY10 expression has also been found in the choroid plexus at both mRNA [127] and protein [128, 129] levels.
Function
ADCY10 activation in astrocytes increases cAMP level, induces glycogenolysis/glycolysis, and provides energy substrate for astrocytes and neurons [123], suggesting an important role in astrocyte-neuron metabolic coupling. Overexpression of ADCY10 in retinal ganglion and dorsal root ganglion cells promotes axonal outgrowth and growth cone elaboration, whereas inhibition of ADCY10 reverses these changes [124, 125], strongly indicating an essential role of ADCY10 in axonal outgrowth. Based on that ADCY10 is expressed in the choroid plexus and CO2 metabolism is linked to cerebrospinal fluid secretion [130], it is hypothesized that ADCY10 regulates cerebrospinal fluid homeostasis. This is evidence showing that increased ADCY10 expression caused by chloral hydrate-induced removal of cilia enhances transcytosis in choroid plexus epithelial cells [131]. Two ADCY10 knockout mouse lines have been generated: C1KO and C2KO, which prevent the expression of C1 and C2 domains, respectively. Both display defective sperm motility due to decreased cAMP production in testis and spermatozoa [126, 132], highlighting a crucial role of ADCY10 in male infertility.
A clinical study revealed that ADCY10 polymorphism is associated with absorptive hypercalciuria and low spinal bone density [133].
Effects of GPCR-ADCY signaling in BBB integrity
The BBB is a unique feature of CNS blood vessels. It is mainly composed of brain endothelial cells, pericytes, astrocytes, microglia, neurons and a non-cellular component—the basal lamina. By tightly regulating what enters/exits the CNS, the BBB maintains brain homeostasis [134, 135].
The effects of GPCR-ADCY signaling in BBB maintenance remain largely unclear, partially due to the complexity of GPCR-ADCY system. There are 10 different ADCY isoforms, which are coupled to distinct GPCRs in different cell types. However, there is evidence suggesting that certain GPCRs may regulate BBB integrity via ADCY activity, although the specific ADCY isoforms involved in each case remain unknown. Below we briefly discuss a few such GPCRs, including sphingosine 1-phosphate receptors (S1PRs), lysophosphatidic acid receptors (LPARs), cannabinoid receptors (CBs), adenosine receptors (ARs), G protein-coupled estrogen receptor 1 (GPER-1), complement C5a receptor (C5aR), somatostatin receptors (SSTRs), glucagon-like peptide-1 receptor (GLP1R), and hydrocarboxylic acid receptor 1 (HCAR1). The expression, G protein subtypes, and functions (in BBB integrity) of these GPCRs are summarized in Table 4.
S1PRs
S1PRs are the receptors for sphingosine 1-phosphate, a signaling sphingolipid with a diverse range of functions. There are 5 subtypes of S1PRs (S1PR1-5), among which four (S1PR1-3 and S1PR5) have been shown to regulate BBB integrity. In the CNS, S1PR1 and S1PR3 are mainly expressed in astrocytes and endothelial cells; S1PR2 is found in pericytes, glial cells, endothelial cells and fibroblasts [136]; and S1PR5 is mainly found in oligodendrocytes and endothelial cells [137, 138]. S1PR1 is coupled to Gαi/o; S1PR2 and S1PR3 are coupled to Gαi/o, Gαq/11 and Gα12/13; and S1PR5 is coupled to Gαi/o and Gα12/13 [139, 140]. Functional studies suggest that S1PR1 regulates BBB integrity. It has been reported that S1PR1/5 agonist siponimod (BAF-312) enhances BBB integrity and increases tight junction protein expression in an in vitro BBB model [141]. Consistent with this finding, S1PR1 functional antagonist (FTY720P) and endothelium-specific knockout of S1PR1 substantially increase BBB permeability to small tracers [142]. There is also evidence showing that S1PR1 can be targeted to facilitate CNS drug delivery. It has been shown that targeting S1PR with S1P and S1PR agonist fingolimod improves CNS drug delivery by reducing basal activity of P-glycoprotein (P-gp), an ATP-driven drug efflux pump, at the BBB and blood–spinal cord barrier, which significantly increases the uptake of radiolabeled P-gp substrates such as verapamil (three-fold), loperamide (five-fold) and paclitaxel (five-fold) [143, 144]. Similarly, pharmacological studies suggest that S1PR2 and S1PR3 function to decrease BBB integrity [145, 146]. S1PR2 antagonist ameliorates oxidative stress-induced cerebrovascular endothelial barrier impairment and reduces BBB leakage after ischemic injury in mice [145]. S1PR3 antagonist CAY10444 attenuates BBB damage by up-regulating tight junction proteins, reduces brain edema, and improves animal behavior in acute intracerebral hemorrhage [146]. S1PR5, on the other hand, seems to promote BBB integrity. It has bene reported that S1PR5-selective agonist improves BBB integrity in vitro and reduces trans-endothelial migration of monocytes. Echoed with these findings, knockdown of S1PR5 compromises BBB integrity and reduces the expression of tight junction proteins, P-gp and BCRP [138]. It should be noted, however, that the specific ADCY isoforms associated with S1PR1-3 and S1PR5 signaling remain unknown.
LPARs
LPARs are the receptors for lysophosphatidic acid (LPA), a bioactive lipid with important functions in physiology and pathology. There are six subtypes of LPARs (LPAR1-6), among which four (LPAR1-3 and LPAR6) have been shown to regulate BBB integrity. LPAR1 is mainly expressed in astrocytes, microglia, oligodendrocytes and endothelial cells; LPAR2 in endothelial cells, neuron and fetal astrocytes; LPAR3 in microglia, astrocytes and endothelial cells; and LPAR6 in microglia, oligodendrocytes, endothelial cells [147, 148]. LPAR1-3 signal through Gαi/o, Gαq/11 and Gα12/13 [147, 149], while LPAR6 signals through Gαs and Gα12/13 [149]. All of these LPARs (LPAR1-3 and LPAR6) function to decrease BBB integrity. It has been shown that LPA decreases tight junction protein expression and transendothelial electrical resistance via LPAR6 in rat brain endothelial cells [150]. Echoed with this finding, intravenous injection of LPA up-regulates LPAR1-3 expression and transiently increases BBB permeability [151]. Additionally, LPA and amitriptyline have been shown to reduce basal P-gp activity through LPAR1 signaling without affecting the activity of MRP2 (multidrug resistance-associated protein 2) or BCRP (breast cancer resistance protein) in both rat brain capillaries and a rat model of amyotrophic lateral sclerosis [152]. Similarly, LPAR ligand gintonin increases tight junction spaces and decreases tight junction protein expression in human brain microvascular endothelial cells. Gintonin has been shown to enter the brain via LPAR1/LPAR3 and enhance BBB permeability to various tracers in vivo [153]. Consistent with these findings, gintonin enhances CNS delivery of donepezil in a time-dependent manner via LPAR1/3 [154]. LPAR inhibitors (HA130, PF8380 and BrP-LPA), on the other hand, reverse BBB damage and enhance tight junction protein expression after ischemic stroke [155].
CBs
CBs have two subtypes (CB1 and CB2), both of which mediate BBB regulation in healthy and injured/diseased conditions. In the CNS, CB1 and CB2 are mainly expressed in neurons and microglia [156, 157]. They can stimulate and/or inhibit various ADCY isoforms independently. It has been shown that activation of CB1 and CB2 by cannabinoid agonists stimulates group II ADCYs (ADCY2, ADCY4 and ADCY7) through Gαs, but inhibits other transmembrane ADCYs (ADCY1, ADCY3, ADCY5, ADCY6, ADCY8 and ADCY9) through Gαi/o and Gαq [158, 159]. In vitro study showed that pharmacological activation of CB1 but not CB2 restored tight junction stability in HIV-1-induced BBB disruption model [160]. Consistent with this finding, CB1-specific cannabinoid agonists inhibited HIV-1 Gp120-mediated BBB damage and prevented down-regulation of tight junction proteins both in vitro and in vivo [160]. Interestingly, CB2-selective agonist O-1966 prevented LPS-induced loss of tight junction proteins in brain microvascular endothelial cells [157]. These findings suggest a protective role of CB1/2 in BBB integrity.
ARs
ARs are the receptors for adenosine, a purine nucleoside released by neurons and glial cells. There are four subtypes of ARs (A1, A2A, A2B and A3), among which AR-A1 and AR-A2A are involved in BBB regulation. In the CNS, AR-A1 and AR-A2A are predominantly expressed in microglia, oligodendrocytes, astrocytes, neurons and endothelial cells [161]. AR-A1 inhibits ADCY activity through Gαi/o, whereas AR-A2A stimulates ADCY activity via Gαs [139, 162]. Although coupled to different G proteins, both ARs function to compromise BBB integrity. It has been shown that activation of AR-A1 and AR-A2A increases BBB permeability and reduces tight junction protein expression [163]. In addition, AR agonists have been used to facilitate the entry of intravenously administered molecules into the brain [164]. For example, AR-A2A agonist lexiscan has been reported to inhibit the expression of P-gp and BCRP and increase the accumulation of the epirubicin, a P-gp substrate and chemotherapeutic drug, in mouse brain [165]. In addition, lexiscan has also been shown to increase paracellular leakage in cultured brain endothelial cells, enabling a wider therapeutic window for therapeutics to enter the brain [162].
GPER-1
GPER-1, also known as GPR30, is a novel estrogen receptor highly expressed in neurons [166]. Activation of GPER-1 stimulates ADCY activity via Gαs and Gβγ [167]. GPER-1 activation has been shown to reduce BBB leakage and increase tight junction proteins after ischemic injury [168], highlighting a protective role in BBB integrity.
C5aR
C5aR is the receptor for C5a, a potent proinflammatory peptide generated during complement system activation. In the CNS, C5aR is constitutively expressed in astrocytes, microglia and neurons. Activation of C5aR inhibits ADCY activity via Gαi/o [169, 170]. In vitro study showed that activation of C5aR increased BBB permeability and decreased tight junction protein expression [171], suggesting a detrimental role of C5aR in BBB integrity.
SSTRs
SSTRs mediate the effect of somatostatin, a neuropeptide with important functions in modulating cortical circuits and cognition. There are five subtypes of SSTRs (SSTR1-5), all of which are mainly expressed in neurons and inhibit ADCY activity via Gαi/o and Gβγ [172, 173]. In vitro study showed that somatostatin and selective SSTR agonists maintained BBB integrity and restored ZO-1 organization in cytokine- and LPS-treated human brain endothelial cells [174], suggesting that SSTR activation protects BBB integrity.
GLP1R
GLP1R mediates the function of glucagon-like peptide-1, a short peptide hormone secreted by intestinal enteroendocrine L cells and certain neurons. In the CNS, GLP1R is mainly expressed in astrocytes, neurons, microglia and endothelial cells [175]. Activation of GLP1R stimulates ADCY activity via Gαs [176]. In vitro study showed that GLP-1 increased tight junction protein expression and decreased paracellular permeability in brain capillary endothelial cells via cAMP-PKA signaling pathway [177], indicating a protective role in BBB integrity.
HCAR1
HCAR1, also known as GPR81, is expressed in endothelial cells, astrocytes and neurons [178, 179]. It inhibits ADCY activity through Gαi/o [178, 179]. In vitro study showed that LPS reduced the expression of HCAR1 and tight junction proteins and increased BBB permeability in rat brain microvascular endothelial cells [180]. In addition, activation of HCAR1 stimulates mitochondrial biogenesis and regulates monocarboxylate transporter expression in brain endothelial cells, which are crucial for the metabolism and function of the neurovascular unit [181, 182]. These results suggest a possible role of HCAR1 in BBB maintenance.
Conclusions and future directions
Since the identification of cAMP as an important second messenger, substantial progress has been made with respect to the structure, expression, regulation and functions of ADCYs. There are, however, still several key questions that need to be answered in future research.
First, the expression profiles of ADCYs at the protein level remain largely unknown, possibly due to the lack of isoform-specific antibodies. Current knowledge on ADCY expression is mainly at the mRNA level. Future research should focus on addressing this bottleneck by developing isoform-specific antibodies and innovative genetic tools (e.g., reporter mouse lines).
Second, there is a lack of genetic knockout/overexpression models for certain ADCY isoforms. For example, the phenotypes of ADCY2, ADCY4 and ADCY7 global knockout mice as well as ADCY2, ADCY3, ADCY4 and ADCY10 overexpression mice remain unknown. In addition, the cell-specific conditional knockout mice for many ADCY isoforms are still lacking. Furthermore, there are currently few compound knockout mice available, which are useful in dissecting the roles of ADCYs with compensatory/overlapping functions. Generating these genetic tools will enable loss-of-function studies and substantially move the field forward.
Third, there is a lack of isoform-specific pharmacological reagents for ADCYs. Incomplete pharmacological characterization of mammalian ADCYs has resulted in misconceptions/errors in the selectivity of certain compounds [183]. The lack of selectivity and potency of pharmacological reagents has often resulted in inaccurate or even faulty conclusions in ADCY research. Future research should focus on screening and identifying isoform-specific ADCY activators and inhibitors.
Fourth, the association profiles between ADCYs and GPCRs in different cell types remain unknown. Establishing a cell-specific GPCR-ADCY association profile will significantly enrich our knowledge in GPCR-ADCY signaling. Together with the cell-specific expression profiles of GPCRs and ADCYs, this association profile makes it possible to determine the crosstalk between various signaling pathways, promoting more accurate and safer treatments.
Fifth, more efficient and specific detection approaches are needed for ADCY research. Although multiple methods exist to measure cAMP levels in cells, these approaches are mostly end-point assays and unable to reflect cAMP levels in real time or that generated by a specific ADCY isoform [184, 185]. Although fluorescence resonance energy transfer (FRET)-based cAMP biosensors allow the cAMP detection in living cells in real time [186, 187], they usually have low efficiency and sensitivity. More sensitive and rapid approaches are needed. In addition, biosensors that are able to target different subcellular compartments may help study localized cAMP dynamics [188, 189].
Last, the functions of ADCYs are not fully understood. For example, the roles of ADCYs in CNS barriers (e.g., BBB, blood-CSF barrier and brain-CSF barrier) and the underlying molecular mechanisms are only partially understood. In addition, the functions of ADCY isoforms in human diseases and the links between ADCY gene polymorphisms and human diseases remain largely unknown. With the generation of novel tools (isoform-specific antibodies and genetic mouse lines), we expect to determine the functional significance of each ADCY isoform in a cell-specific manner.
Availability of data and materials
Not applicable.
Abbreviations
- ADCYs:
-
Adenylyl cyclases
- ARs:
-
Adenosine receptors
- BBB:
-
Blood–brain barrier
- cAMP:
-
Cyclic adenosine 3′,5′-monophosphate (cAMP)
- CaMKII:
-
Calcium/calmodulin-dependent protein kinase II
- CaMKIV:
-
Calcium/calmodulin-dependent protein kinase IV
- C5aR:
-
Complement C5a receptor
- CBs:
-
Cannabinoid receptors
- GLP1R:
-
Glucagon-like peptide-1 receptor
- GPCRs:
-
G protein-coupled receptors
- GPER-1:
-
G protein-coupled estrogen receptor 1
- GWAS:
-
Genome wide analysis studies
- HCAR1:
-
Hydrocarboxylic acid receptor 1
- LTP:
-
Long-term potentiation
- LPARs:
-
Lysophosphatidic acid receptors
- OPC:
-
Oligodendrocyte’s precursor cells
- PKA:
-
Protein kinase A
- PKC:
-
Protein kinase C
- RGS2:
-
Regulator of G protein signaling 2
- SSTRs:
-
Somatostatin receptors
- S1PRs:
-
Sphingosine 1-phosphate receptors
References
Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, et al. A family of cAMP-binding proteins that directly activate Rap1. Science. 1998;282:2275–9.
Yarwood SJ. Special issue on “New Advances in Cyclic AMP Signalling”—an editorial overview. Cells. 2020;9:2274.
Serezani CH, Ballinger MN, Aronoff DM, Peters-Golden M. Cyclic AMP: Master regulator of innate immune cell function. Am J Respir Cell Mol Biol. 2008;39:127–32.
Kleuss C. Adenylate cyclase. Pharm Compr Pharmacol Ref. 2007;1–12.
Linder JU, Schultz JE. The class III adenylyl cyclases: multi-purpose signalling modules. Cell Signal. 2003;15:1081–9.
Pastan I, Perlman R. Cyclic adenosine monophosphate in bacteria: in many bacteria the synthesis of inducible enzymes requires this cyclic nucleotide. Science. 1970;169:339–44. https://doi.org/10.1126/science.169.3943.339.
Shimada T, Fujita N, Yamamoto K, Ishihama A. Novel roles of camp receptor protein (CRP) in regulation of transport and metabolism of carbon sources. PLoS ONE. 2011;6:e20081.
Ahuja N, Kumar P, Bhatnagar R. The adenylate cyclase toxins. Crit Rev Microbiol. 2004;30:187–96.
Gallagher DT, Smith NN, Kim SK, Heroux A, Robinson H, Reddy PT. Structure of the class IV adenylyl cyclase reveals a novel fold. J Mol Biol. 2006;362:114–22.
Téllez-Sosa J, Soberón N, Vega-Segura A, Torres-Márquez ME, Cevallos MA. The Rhizobium etli cyaC product: characterization of a novel adenylate cyclase class. J Bacteriol. 2002;184:3560–8.
Dessauer CW, Watts VJ, Ostrom RS, Conti M, Dove S, Seifert R. International union of basic and clinical pharmacology. CI. structures and small molecule modulators of mammalian adenylyl cyclases. Pharmacol Rev. 2017;69:96–139.
Brust TF. Second messengers | adenylyl cyclases. Encycl Biol Chem. 2021;III:496–502.
Kleinboelting S, Diaz A, Moniot S, Van Den Heuvel J, Weyand M, Levin LR, et al. Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate. Proc Natl Acad Sci USA. 2014;111:3727–32.
Hanoune J, Pouille Y, Tzavara E, Shen T, Lipskaya L, Miyamoto N, et al. Adenylyl cyclases: structure, regulation and function in an enzyme superfamily. Mol Cell Endocrinol. 1997;128:179–94.
Defer N, Best-Belpomme M, Hanoune J. Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. Am J Physiol Physiol. 2000;279:F400–16.
Sawin PB, Gadbois DS. Genetic influences upon the sex ratio in the rabbit. Genetics. 1947;32:286–302.
Sadana R, Dessauer CW. Physiological roles for G protein-regulated adenylyl cyclase isoforms: insights from knockout and overexpression studies. Neurosignals. 2009;17:5–22.
Dessauer CW. Adenylyl cyclase. Encycl Signal Mol. 2018. https://doi.org/10.1007/978-3-319-67199-4_101571.
Wong ST, Trinh K, Hacker B, Chan GCK, Lowe G, Gaggar A, et al. Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Neuron. 2000;27:487–97.
Yan SZ, Huang ZH, Andrews RK, Tang WJ. Conversion of forskolin-insensitive to forskolin-sensitive (mouse-type IX) adenylyl cyclase. Mol Pharmacol. 1998;53:182–7.
Antoni FA. The chilling of adenylyl cyclase 9 and its translational potential. Cell Signal. 2020;70:109589. https://doi.org/10.1016/j.cellsig.2020.109589.
Tresguerres M, Levin LR, Buck J. Intracellular cAMP signaling by soluble adenylyl cyclase. Kidney Int. 2011;79:1277–88. https://doi.org/10.1038/ki.2011.95.
Jaiswal BS, Conti M. Calcium regulation of the soluble adenylyl cyclase expressed in mammalian spermatozoa. Proc Natl Acad Sci USA. 2003;100:10676–81.
Zippin JH, Farrell J, Huron D, Kamenetsky M, Hess KC, Fischman DA, et al. Bicarbonate-responsive “soluble” adenylyl cyclase defines a nuclear cAMP microdomain. J Cell Biol. 2004;164:527–34.
Acin-Perez R, Salazar E, Kamenetsky M, Buck J, Levin LR, Manfredi G. Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab. 2009;9:265–76.
Acin-Perez R, Salazar E, Brosel S, Yang H, Schon EA, Manfredi G. Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects. EMBO Mol Med. 2009;1:392–406.
Wu ZL, Thomas SA, Villacres EC, Xia Z, Simmons ML, Chavkin C, et al. Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice. Proc Natl Acad Sci USA. 1995;92:220–4.
Wang H, Ferguson GD, Pineda VV, Cundiff PE, Storm DR. Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP. Nat Neurosci. 2004;7:635–42.
Wang H, Pineda VV, Chan GCK, Wong ST, Muglia LJ, Storm DR. Type 8 adenylyl cyclase is targeted to excitatory synapses and required for mossy fiber long-term potentiation. J Neurosci. 2003;23:9710–8.
Wong ST, Athos J, Figueroa XA, Pineda VV, Schaefer ML, Chavkin CC, et al. Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron. 1999;23:787–98.
Zheng F, Zhang M, Ding Q, Sethna F, Yan L, Moon C, et al. Voluntary running depreciates the requirement of Ca2+-stimulated cAMP signaling in synaptic potentiation and memory formation. Learn Mem. 2016;23:442–9.
Yamamoto M, Götz ME, Ozawa H, Luckhaus C, Saito T, Rösler M, et al. Hippocampal level of neural specific adenylyl cyclase type I is decreased in Alzheimer’s disease. Biochim Biophys Acta - Mol Basis Dis. 2000;1535:60–8.
Schaefer ML, Wong ST, Wozniak DF, Muglia LM, Liauw JA, Zhuo M, et al. Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient mice. J Neurosci. 2000;20:4809–20.
Bernabucci M, Zhuo M. Calcium activated adenylyl cyclase AC8 but not AC1 is required for prolonged behavioral anxiety. Mol Brain Molecular Brain. 2016;9:1–12. https://doi.org/10.1186/s13041-016-0239-x.
Razzoli M, Andreoli M, Maraia G, Di Francesco C, Arban R. Functional role of calcium-stimulated adenylyl cyclase 8 in adaptations to psychological stressors in the mouse: implications for mood disorders. Neuroscience. 2010;170:429–40.
Zhang P, Xiang N, Chen Y, Śliwerska E, McInnis MG, Burmeister M, et al. Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs. Bipolar Disord. 2010;12:786–92.
Wolf EJ, Rasmusson AM, Mitchell KS, Logue MW, Baldwin CT, Miller MW. A genome-wide Association study of clinical symptoms of dissociation in a trauma-exposed sample. Depress Anxiety. 2014;31:352–60. https://doi.org/10.1002/da.22260.
Wang Z, Phan T, Storm DR. The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of camp signaling in primary cilia. J Neurosci. 2011;31:5557–61.
Chen X, Luo J, Leng Y, Yang Y, Zweifel LS, Palmiter RD, et al. Ablation of type III adenylyl cyclase in mice causes reduced neuronal activity, altered sleep pattern, and depression-like phenotypes. Biol Psychiatry. 2016;80:836–48.
Iwamoto T, Okumura S, Iwatsubo K, Kawabe JI, Ohtsu K, Sakai I, et al. Motor dysfunction in type 5 adenylyl cyclase-null mice. J Biol Chem. 2003;278:16936–40. https://doi.org/10.1074/jbc.C300075200.
Joeyen-Waldorf J, Nikolova YS, Edgar N, Walsh C, Kota R, Lewis DA, et al. Adenylate cyclase 7 is implicated in the biology of depression and modulation of affective neural circuitry. Biol Psychiatry. 2012;71:627–32.
Hines LM, Hoffman PL, Bhave S, Saba L, Kaiser A, Snell L, et al. A sex-specific role of type VII adenylyl cyclase in depression. J Neurosci. 2006;26:12609–19.
Nicol X, Muzerelle A, Bachy I, Ravary A, Gaspar P. Spatiotemporal localization of the calcium-stimulated adenylate cyclases, AC1 and AC8, during mouse brain development. J Comp Neurol. 2005;486:281–94.
Xia Z, Choi E-J, Wang F, Blazynski C, Storm DR. Type I calmodulin-sensitive adenylyl cyclase is neural specific. J Neurochem. 1993;60:305–11.
Brain RNA-Seq. https://brainrnaseq.org/. Accessed 29 Nov 2021.
Single Cell RNA-seq Gene Expression Data. https://betsholtzlab.org/VascularSingleCells/database.html. Accessed 29 Nov 2021.
Konur S, Ghosh A. Calcium signaling and the control of dendritic development. Neuron. 2005;46:401–5.
Mons N, Segu L, Nogues X, Buhot MC. Effects of age and spatial learning on adenylyl cyclase mRNA expression in the mouse hippocampus. Neurobiol Aging. 2004;25:1095–106.
Mons N, Guillou JL, Decorte L, Jaffard R. Spatial learning induces differential changes in calcium/calmodulin-stimulated (ACI) and calcium-insensitive (ACII) adenylyl cyclases in the mouse hippocampus. Neurobiol Learn Mem. 2003;79:226–35.
Storm DR, Hansel C, Hacker B, Parent A, Linden DJ. Impaired cerebellar long-term potentiation in type I adenylyl cyclase mutant mice. Neuron. 1998;20:1199–210.
Villacres EC, Wong ST, Chavkin C, Storm DR. Type I adenylyl cyclase mutant mice have impaired mossy fiber long-term potentiation. J Neurosci. 1998;18:3186–94. https://doi.org/10.1523/JNEUROSCI.18-09-03186.1998.
Wei F, Qiu CS, Kim SJ, Muglia L, Maas JW, Pineda VV, et al. Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron. 2002;36:713–26.
Sethna F, Feng W, Ding Q, Robison AJ, Feng Y, Wang H. Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model. Nat Commun. 2017;8:14359.
Ansar M, Chahrour MH, AminudDin M, Arshad M, Haque S, Pham TL, et al. DFNB44, a novel autosomal recessive non-syndromic hearing impairment locus, maps to chromosome 7p14.1-q11.22. Hum Hered. 2004;57:195–9.
Santos-Cortez RLP, Lee K, Giese AP, Ansar M, Amin-Ud-Din M, Rehn K, et al. Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. Hum Mol Genet. 2014;23:3289–98. https://doi.org/10.1093/hmg/ddu042.
Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, Heilbronner U, et al. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: a genome-wide association study. JAMA Psychiat. 2018;75:65–74.
GWAS CATALOG. https://www.ebi.ac.uk/gwas/genes/ADCY1. Accessed 4 Dec 2021.
Visel A, Alvarez-Bolado G, Thaller C, Eichele G. Comprehensive analysis of the expression patterns of the adenylate cyclase gene family in the developing and adult mouse brain. J Comp Neurol. 2006;496:684–97. https://doi.org/10.1002/cne.20953.
Baker LP, Nielsen MD, Impey S, Hacker BM, Poser SW, Chan MYM, et al. Regulation and immunohistochemical localization of βγ-stimulated adenylyl cyclases in mouse hippocampus. J Neurosci. 1999;19:180–92.
Lipskaia L, Djiane A, Defer N, Hanoune J. Different expression of adenylyl cyclase isoforms after retinoic acid induction of P19 teratocarcinoma cells. FEBS Lett. 1997;415:275–80. https://doi.org/10.1016/S0014-5793(97)01001-6.
Lipskaia L, Grépin C, Defer N, Hanoune J. Adenylyl cyclase activity and gene expression during mesodermal differentiation of the P19 embryonal carcinoma cells. J Cell Physiol. 1998;176:50–6.
McCarthy MJ, Liang S, Spadoni AD, Kelsoe JR, Simmons AN. Whole brain expression of bipolar disorder associated genes: structural and genetic analyses. PLoS ONE. 2014;9:e100204.
Mullins N, Forstner AJ, O’Connell KS, Coombes B, Coleman JRI, Qiao Z, et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet. 2021;53:817–29.
Meier SM, Trontti K, Purves KL, Als TD, Grove J, Laine M, et al. Genetic variants associated with anxiety and stress-related disorders: a genome-wide association study and mouse-model study. JAMA Psychiat. 2019;76:924–32.
Price T, Brust TF. Adenylyl cyclase 7 and neuropsychiatric disorders: a new target for depression? Pharmacol Res. 2019;143:106–12. https://doi.org/10.1016/j.phrs.2019.03.015.
Peyrot WJ, Price AL. Identifying loci with different allele frequencies among cases of eight psychiatric disorders using CC-GWAS. Nat Genet. 2021;53:445–54.
Zhou Y, Qiu L, Sterpka A, Wang H, Chu F, Chen X. Comparative phosphoproteomic profiling of type III adenylyl cyclase knockout and control, male, and female mice. Front Cell Neurosci. 2019;13:1–21.
Hu ML, Zhang WW, Cao H, Zhang YQ. Expression pattern of type 3 adenylyl cyclase in rodent dorsal root ganglion and its primary afferent terminals. Neurosci Lett. 2019;692:16–22.
Bishop GA, Berbari NF, Lewis J, Mykytyn K. Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J Comp Neurol. 2007;505:562–71. https://doi.org/10.1002/cne.21510.
Zhang Z, Yang D, Zhan M, Zhu N, Zhou Y, Storm DR, et al. Deletion of type 3 adenylyl cyclase perturbs the postnatal maturation of olfactory sensory neurons and olfactory cilium ultrastructure in mice. Front Cell Neurosci. 2017;11:1–15.
Wang Z, Sindreu CB, Li V, Nudelman A, Chan GCK, Storm DR. Pheromone detection in male mice depends on signaling through the type 3 adenylyl cyclase in the main olfactory epithelium. J Neurosci. 2006;26:7375–9.
Wang Z, Storm DR. Maternal behavior is impaired in female mice lacking type 3 adenylyl cyclase. Neuropsychopharmacology. 2011;36:772–81. https://doi.org/10.1038/npp.2010.211.
Banizs B, Pike MM, Millican CL, Ferguson WB, Komlosi P, Sheetz J, et al. Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus. Development. 2005;132:5329–39.
Saeed S, Bonnefond A, Tamanini F, Mirza MU, Manzoor J, Janjua QM, et al. Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Nat Genet. 2018;50:175–9. https://doi.org/10.1038/s41588-017-0023-6.
Warrington NM, Howe LD, Paternoster L, Kaakinen M, Herrala S, Huikari V, et al. A genome-wide association study of body mass index across early life and childhood. Int J Epidemiol. 2015;44:700–12.
Stergiakouli E, Gaillard R, Tavaré JM, Balthasar N, Loos RJ, Taal HR, et al. Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3. Obesity. 2014;22:2252–9.
Wray NR, Pergadia ML, Blackwood DHR, Penninx BWJH, Gordon SD, Nyholt DR, et al. Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Mol Psychiatry. 2012;17:36–48. https://doi.org/10.1038/mp.2010.109.
Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47:979–86.
Hulur I, Gamazon ER, Skol AD, Xicola RM, Llor X, Onel K, et al. Enrichment of inflammatory bowel disease and colorectal cancer risk variants in colon expression quantitative trait loci. BMC Genomics. 2015;16:1–15.
Sanabra C, Mengod G. Neuroanatomical distribution and neurochemical characterization of cells expressing adenylyl cyclase isoforms in mouse and rat brain. J Chem Neuroanat. 2011;41:43–54. https://doi.org/10.1016/j.jchemneu.2010.11.001.
Kittikulsuth W, Stuart D, Kohan DE. Adenylyl cyclase 4 does not regulate collecting duct water and sodium handling. Physiol Rep. 2014;2:1–9.
de Gortari P, Mengod G. Dopamine D1, D2 and mu-opioid receptors are co-expressed with adenylyl cyclase 5 and phosphodiesterase 7B mRNAs in striatal rat cells. Brain Res. 2010;1310:37–45. https://doi.org/10.1016/j.brainres.2009.11.009.
Kheirbek MA, Britt JP, Beeler JA, Ishikawa Y, McGehee DS, Zhuang X. Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning. J Neurosci. 2009;29:12115–24.
Zhang Y, Lu W, Wang Z, Zhang R, Xie Y, Guo S, et al. Reduced neuronal cAMP in the nucleus accumbens damages blood-brain barrier integrity and promotes stress vulnerability. Biol Psychiatry. 2020;87:526–37. https://doi.org/10.1016/j.biopsych.2019.09.027.
Kim K-S, Han P-L. Mice lacking adenylyl cyclase-5 cope badly with repeated restraint stress. J Neurosci Res. 2009;87:2983–93. https://doi.org/10.1002/jnr.22119.
Lee KW, Hong JH, Choi IY, Che Y, Lee JK, Yang SD, et al. Impaired D2 dopamine receptor function in mice lacking type 5 adenylyl cyclase. J Neurosci. 2002;22:7931–40.
Tang T, Lai NC, Roth DM, Drumm J, Guo T, Lee KW, et al. Adenylyl cyclase type V deletion increases basal left ventricular function and reduces left ventricular contractile responsiveness to β-adrenergic stimulation. Basic Res Cardiol. 2006;101:117–26. https://doi.org/10.1007/s00395-005-0559-y.
Okumura S, Kawabe JI, Yatani A, Takagi G, Lee MC, Hong C, et al. Type 5 adenylyl cyclase disruption alters not only sympathetic but also parasympathetic and calcium-mediated cardiac regulation. Circ Res. 2003;93:364–71.
Okumura S, Vatner DE, Kurotani R, Bai Y, Gao S, Yuan Z, et al. Disruption of type 5 adenylyl cyclase enhances desensitization of cyclic adenosine monophosphate signal and increases Akt signal with chronic catecholamine stress. Circulation. 2007;116:1776–83.
Yan L, Vatner DE, O’Connor JP, Ivessa A, Ge H, Chen W, et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell. 2007;130:247–58.
Vatner SF, Pachon RE, Vatner DE. Inhibition of adenylyl cyclase type 5 increases longevity and healthful aging through oxidative stress protection. Oxid Med Cell Longev. 2015;2015:250310.
Chen Y-Z. Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylate cyclase 5. Arch Neurol. 2012;69:630. https://doi.org/10.1001/archneurol.2012.54.
Okamoto N, Miya F, Kitai Y, Tsunoda T, Kato M, Saitoh S, et al. Homozygous ADCY5 mutation causes early-onset movement disorder with severe intellectual disability. Neurol Sci. 2021;42:2975–8.
Ferrini A, Steel D, Barwick K, Kurian MA. An update on the phenotype, genotype and neurobiology of ADCY5-related disease. Mov Disord. 2021;36:1104–14.
Chen YZ, Friedman JR, Chen DH, Chan GC-K, Bloss CS, Hisama FM, et al. Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. Ann Neurol. 2014;75:542–9. https://doi.org/10.1002/ana.24119.
Lai NC, Roth DM, Gao MH, Tang T, Dalton N, Lai YY, et al. Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure. Circulation. 2004;110:330–6.
Tang T, Gao MH, Lai NC, Firth AL, Takahashi T, Guo T, et al. Adenylyl cyclase type 6 deletion decreases left ventricular function via impaired calcium handling. Circulation. 2008;117:61–9.
Rieg T, Tang T, Murray F, Schroth J, Insel PA, Fenton RA, et al. Adenylate cyclase 6 determines cAMP formation and aquaporin-2 phosphorylation and trafficking in inner medulla. J Am Soc Nephrol. 2010;21:2059–68. https://doi.org/10.1681/ASN.2010040409.
Rieg T, Tang T, Uchida S, Hammond HK, Fenton RA, Vallon V. Adenylyl cyclase 6 enhances NKCC2 expression and mediates vasopressin-induced phosphorylation of NKCC2 and NCC. Am J Pathol. 2013;182:96–106. https://doi.org/10.1016/j.ajpath.2012.09.014.
Laquérriere A, Maluenda J, Camus A, Fontenas L, Dieterich K, Nolent F, et al. Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. Hum Mol Genet. 2014;23:2279–89.
Agolini E, Cherchi C, Bellacchio E, Martinelli D, Cocciadiferro D, Cutrera R, et al. Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6. Clin Genet. 2020;97:649–54.
Li W, Sang M, Hao X, Jia L, Wang Y, Shan B. Gene expression and DNA methylation analyses suggest that immune process-related ADCY6 is a prognostic factor of luminal-like breast cancer. J Cell Biochem. 2020;121:3537–46. https://doi.org/10.1002/jcb.29633.
Mons N, Yoshimura M, Ikeda H, Hoffman PL, Tabakoff B. Immunological assessment of the distribution of Type VII adenylyl cyclase in brain. Brain Res. 1998;788:251–61.
Cruz MT, Bajo M, Maragnoli ME, Tabakoff B, Siggins GR, Roberto M. Type 7 adenylyl cyclase is involved in the ethanol and CRF sensitivity of GABAergic synapses in mouse central amygdala. Front Neurosci. 2011;4:1–7.
Pronko SP, Saba LM, Hoffman PL, Tabakoff B. Type 7 adenylyl cyclase-mediated hypothalamic-pituitary-adrenal axis responsiveness: influence of ethanol and sex. J Pharmacol Exp Ther. 2010;334:44–52.
Jiang LI, Sternweis PC, Wang JE. Zymosan activates protein kinase A via adenylyl cyclase VII to modulate innate immune responses during inflammation. Mol Immunol. 2013;54:14–22.
Duan B, Davis R, Sadat EL, Collins J, Sternweis PC, Yuan D, et al. Distinct roles of adenylyl cyclase VII in regulating the immune responses in mice. J Immunol. 2010;185:335–44. https://doi.org/10.4049/jimmunol.0903474.
Luo Y, De Lange KM, Jostins L, Moutsianas L, Randall J, Kennedy NA, et al. Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7. Nat Genet. 2017;49:186–92.
Li YR, Li J, Zhao SD, Bradfield JP, Mentch FD, Maggadottir SM, et al. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat Med. 2015;21:1018–27.
Wieczorek L, Maas JW, Muglia LM, Vogt SK, Muglia LJ. Temporal and regional regulation of gene expression by calcium-stimulated adenylyl cyclase activity during fear memory. PLoS ONE. 2010;5:e13385.
Xu H, Leinwand SG, Dell AL, Fried-Cassorla E, Raper JA. The calmodulin-stimulated adenylate cyclase ADCY8 sets the sensitivity of zebrafish retinal axons to midline repellents and is required for normal midline crossing. J Neurosci. 2010;30:7423–33.
Naß J, Efferth T. Pharmacogenetics and pharmacotherapy of military personnel suffering from post-traumatic stress disorder. Curr Neuropharmacol. 2016;15:831–60.
GWAS Catalog. https://www.ebi.ac.uk/gwas/genes/ADCY8. Accessed 4 Dec 2021.
Antoni FA, Palkovits M, Simpson J, Smith SM, Leitch AL, Rosie R, et al. Ca2+/calcineurin-lnhibited adenylyl cyclase, highly abundant in forebrain regions, is important for learning and memory. J Neurosci. 1998;18:9650–61.
Premont RT, Matsuoka I, Mattei MG, Pouille Y, Defer N, Hanoune J. Identification and characterization of a widely expressed form of adenylyl cyclase. J Biol Chem. 1996;271:13900. https://doi.org/10.1074/jbc.271.23.13900.
Li Y, Baldwin TA, Wang Y, Subramaniam J, Carbajal AG, Brand CS, et al. Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction. Sci Rep. 2017;7:1–11.
Liu L, Das S, Losert W, Parent CA. MTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion. Dev Cell. 2010;19:845–57. https://doi.org/10.1016/j.devcel.2010.11.004.
Huang B, Zhao J, Lei Z, Shen S, Li D, Shen GX, et al. miR-142-3p restricts cAMP production in CD4+CD25- T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep. 2009;10:180–5.
Yucesoy B, Kaufman KM, Lummus ZL, Weirauch MT, Zhang G, Cartier A, et al. Genome-wide association study identifies novel loci associated with diisocyanate-induced occupational asthma. Toxicol Sci. 2015;146:192–201. https://doi.org/10.1093/toxsci/kfv084.
Kim SH, Ye YM, Lee HY, Sin HJ, Park HS. Combined pharmacogenetic effect of ADCY9 and ADRB2 gene polymorphisms on the bronchodilator response to inhaled combination therapy. J Clin Pharm Ther. 2011;36:399–405.
Toyota T, Hattori E, Meerabux J, Yamada K, Saito K, Shibuya H, et al. Molecular analysis, mutation screening, and association study of adenylate cyclase type 9 gene (ADCY9) in mood disorders. Am J Med Genet. 2002;114:84–92.
Tardif JC, Rheaúme E, Lemieux Perreault LP, Grégoire JC, Feroz Zada Y, Asselin G, et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet. 2015;8:372–82. https://doi.org/10.1161/CIRCGENETICS.114.000663.
Choi HB, Gordon GRJ, Zhou N, Tai C, Rungta RL, Martinez J, et al. Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase. Neuron. 2012;75:1094–104.
Wu KY, Zippin JH, Huron DR, Kamenetsky M, Hengst U, Buck J, et al. Soluble adenylyl cyclase is required for netrin-1 signaling in nerve growth cones. Nat Neurosci. 2006;9:1257–64.
Corredor RG, Trakhtenberg EF, Pita-Thomas W, Jin X, Hu Y, Goldberg JL. Soluble adenylyl cyclase activity is necessary for retinal ganglion cell survival and axon growth. J Neurosci. 2012;32:7734–44.
Chen J, Martinez J, Milner TA, Buck J, Levin LR. Neuronal expression of soluble adenylyl cyclase in the mammalian brain. Brain Res. 2013;1518:1–8.
Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445:168–76.
Chen Y, Cann MJ, Litvin TN, Iourgenko V, Sinclair ML, Levin LR, et al. Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. Science. 2000;289:625–8. https://doi.org/10.1126/science.289.5479.625.
Mittag TW, Guo WB, Kobayashi K. Bicarbonate-activated adenylyl cyclase in fluid-transporting tissues. Am J Physiol Physiol. 1993;264:F1060–4. https://doi.org/10.1152/ajprenal.1993.264.6.F1060.
Ames A, Higashi K, Nesbett FB. Effects of Pco2 acetazolamide and ouabain on volume and composition of choroid-plexus fluid. J Physiol. 1965;181:516–24.
Narita K, Kawate T, Kakinuma N, Takeda S. Multiple primary cilia modulate the fluid transcytosis in choroid plexus epithelium. Traffic. 2010;11:287–301.
Schmid A, Meili D, Salathe M. Soluble adenylyl cyclase in health and disease. Biochim Biophys Acta - Mol Basis Dis. 2014;1842:2584–92. https://doi.org/10.1016/j.bbadis.2014.07.010.
Reed BY, Gitomer WL, Heller HJ, Ming CH, Lemke M, Padalino P, et al. Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density. J Clin Endocrinol Metab. 2002;87:1476–85.
Weiss N, Miller F, Cazaubon S, Couraud PO. The blood–brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta - Biomembr. 2009;1788:842–57. https://doi.org/10.1016/j.bbamem.2008.10.022.
Segarra M, Aburto MR, Acker-Palmer A. Blood–brain barrier dynamics to maintain brain homeostasis. Trends Neurosci. 2021;44:393–405. https://doi.org/10.1016/j.tins.2020.12.002.
Pluimer BR, Colt M, Zhao Z. G Protein-coupled receptors in the mammalian blood-brain barrier. Front Cell Neurosci. 2020;14:1–9.
Prager B, Spampinato SF, Ransohoff RM. Sphingosine 1-phosphate signaling at the blood–brain barrier. Trends Mol Med. 2015;21:354–63. https://doi.org/10.1016/j.molmed.2015.03.006.
van Doorn R, Lopes Pinheiro MA, Kooij G, Lakeman K, van het Hof B, van der Pol SMA, et al. Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier. J Neuroinflammation. 2012;9:133.
González-Mariscal L, Raya-Sandino A, González-González L, Hernández-Guzmán C. Relationship between G proteins coupled receptors and tight junctions. Tissue Barriers. 2018;6:1–37.
Lucaciu A, Brunkhorst R, Pfeilschifter JM, Pfeilschifter W, Subburayalu J. The S1P–S1PR axis in neurological disorders-insights into current and future therapeutic perspectives. Cells. 2020;9:1–37.
Spampinato SF, Merlo S, Sano Y, Kanda T, Sortino MA. Protective effect of the sphingosine-1 phosphate receptor agonist siponimodon disrupted blood brain barrier function. Biochem Pharmacol. 2021;186:114465.
Yanagida K, Liu CH, Faraco G, Galvani S, Smith HK, Burg N, et al. Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1. Proc Natl Acad Sci USA. 2017;114:4531–6.
Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proc Natl Acad Sci USA. 2012;109:15930–5.
Cartwright TA, Campos CR, Cannon RE, Miller DS. Mrp1 is essential for sphingolipid signaling to p-glycoprotein in mouse blood-brain and blood-spinal cord barriers. J Cereb Blood Flow Metab. 2013;13:381–8.
Cao C, Dai L, Mu J, Wang X, Hong Y, Zhu C, et al. S1PR2 antagonist alleviates oxidative stress-enhanced brain endothelial permeability by attenuating p38 and Erk1/2-dependent cPLA2 phosphorylation. Cell Signal. 2019;53:151–61. https://doi.org/10.1016/j.cellsig.2018.09.019.
Xu D, Gao Q, Wang F, Peng Q, Wang G, Wei Q, et al. Sphingosine-1-phosphate receptor 3 is implicated in BBB injury via the CCL2-CCR2 axis following acute intracerebral hemorrhage. CNS Neurosci Ther. 2021;27:674–86.
Yung YC, Stoddard NC, Mirendil H, Chun J. Lysophosphatidic acid signaling in the nervous system. Neuron. 2015;85:669–82.
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. Brain RNA-Seq. An RNA-sequencing Transcr. splicing database glia, neurons, Vasc Cells Cereb Cortex. 2014, p. 11929–47. https://brainrnaseq.org/. Accessed 28 Dec 2021.
Geraldo LHM, Spohr de TCL, Amaral do RF, Fonseca da ACC, Garcia C, Mendes de FA, et al. Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies. Signal Transduct Target Ther. 2021; https://doi.org/10.1038/s41392-020-00367-5
Masago K, Kihara Y, Yanagida K, Hamano F, Nakagawa S, Niwa M, et al. Lysophosphatidic acid receptor, LPA6, regulates endothelial blood-brain barrier function: implication for hepatic encephalopathy. Biochem Biophys Res Commun. 2018;501:1048–54.
On NH, Savant S, Toews M, Miller DW. Rapid and reversible enhancement of blood–brain barrier permeability using lysophosphatidic acid. J Cereb Blood Flow Metab. 2013;33:1944–54.
Banks DB, Chan GNY, Evans RA, Miller DS, Cannon RE. Lysophosphatidic acid and amitriptyline signal through LPA1R to reduce P-glycoprotein transport at the blood–brain barrier. J Cereb Blood Flow Metab. 2018;38:857–68.
Kim DG, Jang M, Choi SH, Kim HJ, Jhun H, Kim HC, et al. Gintonin, a ginseng-derived exogenous lysophosphatidic acid receptor ligand, enhances blood-brain barrier permeability and brain delivery. Int J Biol Macromol. 2018;114:1325–37. https://doi.org/10.1016/j.ijbiomac.2018.03.158.
Choi SH, Lee NE, Cho HJ, Lee RM, Rhim H, Kim HC, et al. Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors. J Ginseng Res. 2021;45:264–72. https://doi.org/10.1016/j.jgr.2019.12.002.
Bhattarai S, Sharma S, Ara H, Subedi U, Sun G, Li C, et al. Disrupted blood-brain barrier and mitochondrial impairment by autotaxin–lysophosphatidic acid axis in postischemic stroke. J Am Heart Assoc. 2021;10:e021511.
Ibsen MS, Connor M, Glass M. Cannabinoid CB 1 and CB 2 receptor signaling and bias. Cannabis Cannabinoid Res. 2017;2:48–60.
Ramirez SH, Haskó J, Skuba A, Fan S, Dykstra H, McCormick R, et al. Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosci. 2012;32:4004–16.
Rhee MH, Bayewitch M, Avidor-Reiss T, Levy R, Vogel Z. Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes. J Neurochem. 1998;71:1525–34.
Bonhaus DW, Chang LK, Kwan J, Martin GR. Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. J Pharmacol Exp Ther. 1998;287:884–8.
Lu T-S, Avraham HK, Seng S, Tachado SD, Koziel H, Makriyannis A, et al. Cannabinoids inhibit HIV-1 Gp120-mediated insults in brain microvascular endothelial cells. J Immunol. 2008;181:6406–16. https://doi.org/10.4049/jimmunol.181.9.6406.
Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V. Adenosine receptors: expression, function and regulation. Int J Mol Sci. 2014;15:2024–52.
Bynoe MS, Viret C, Yan A, Kim DG. Adenosine receptor signaling: a key to opening the blood–brain door. Fluids Barriers CNS BioMed Central. 2015;12:1–12.
Carman AJ, Mills JH, Krenz A, Kim DG, Bynoe MS. Adenosine receptor signaling modulates permeability of the blood–brain barrier. J Neurosci. 2011;31:13272–80.
Gao X, Qian J, Zheng S, Changyi Y, Zhang J, Ju S, et al. Overcoming the blood-brain barrier for delivering drugs into the brain by using adenosine receptor nanoagonist. ACS Nano. 2014;8:3678–89.
Kim DG, Bynoe MS. A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier. J Clin Invest. 2016;126:1717–33.
Isensee J, Meoli L, Zazzu V, Nabzdyk C, Witt H, Soewarto D, et al. Expression pattern of G protein-coupled receptor 30 in LacZ reporter mice. Endocrinology. 2009;150:1722–3.
Wei W, Chen ZJ, Zhang KS, Yang XL, Wu YM, Chen XH, et al. The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptornegative breast cancer cells in vitro and in vivo. Cell Death Dis. 2014;5:e1428.
Lu D, Qu Y, Shi F, Feng D, Tao K, Gao G, et al. Activation of G protein-coupled estrogen receptor 1 (GPER-1) ameliorates blood-brain barrier permeability after global cerebral ischemia in ovariectomized rats. Biochem Biophys Res Commun. 2016;477:209–14. https://doi.org/10.1016/j.bbrc.2016.06.044.
Sayah S, Jauneau AC, Patte C, Tonon MC, Vaudry H, Fontaine M. Two different transduction pathways are activated by C3a and C5a anaphylatoxins on astrocytes. Mol Brain Res. 2003;112:53–60.
Brandolini L, Grannonico M, Bianchini G, Colanardi A, Sebastiani P, Paladini A, et al. The novel C5aR antagonist DF3016A protects neurons against ischemic neuroinflammatory injury. Neurotox Res. 2019;36:163–74.
Mahajan SD, Parikh NU, Woodruff TM, Jarvis JN, Lopez M, Hennon T, et al. C5a alters blood-brain barrier integrity in a human in vitro model of systemic lupus erythematosus. Immunology. 2015;146:130–43.
Cakir M, Dworakowska D, Grossman A. Somatostatin receptor biology in neuroendocrine and pituitary tumours: Part 1—molecular pathways. J Cell Mol Med. 2010;14:2570–84.
Song YH, Yoon J, Lee SH. The role of neuropeptide somatostatin in the brain and its application in treating neurological disorders. Exp Mol Med. 2021;53:328–38. https://doi.org/10.1038/s12276-021-00580-4.
Basivireddy J, Somvanshi RK, Romero IA, Weksler BB, Couraud PO, Oger J, et al. Somatostatin preserved blood brain barrier against cytokine induced alterations: possible role in multiple sclerosis. Biochem Pharmacol. 2013;86:497–507. https://doi.org/10.1016/j.bcp.2013.06.001.
Shan Y, Tan S, Lin Y, Liao S, Zhang B, Chen X, et al. The glucagon-like peptide-1 receptor agonist reduces inflammation and blood–brain barrier breakdown in an astrocyte-dependent manner in experimental stroke. J Neuroinflamm J. 2019;16:1–20.
Girada SB, Kuna RS, Bele S, Zhu Z, Chakravarthi NR, DiMarchi RD, et al. Gαs regulates glucagon-like peptide 1 receptor-mediated cyclic AMP generation at Rab5 endosomal compartment. Mol Metab. 2017;6:1173–85. https://doi.org/10.1016/j.molmet.2017.08.002.
Fukuda S, Nakagawa S, Tatsumi R, Morofuji Y, Takeshita T, Hayashi K, et al. Glucagon-like peptide-1 strengthens the barrier integrity in primary cultures of rat brain endothelial cells under basal and hyperglycemia conditions. J Mol Neurosci. 2016;59:211–9. https://doi.org/10.1007/s12031-015-0696-1.
de Castro AH, Briquet M, Schmuziger C, Restivo L, Puyal J, Rosenberg N, et al. The lactate receptor HCAR1 modulates neuronal network activity through the activation of G α and G βγ subunits. J Neurosci. 2019;39:4422–33. https://doi.org/10.1523/JNEUROSCI.2092-18.2019.
Morland C, Lauritzen KH, Puchades M, Holm-Hansen S, Andersson K, Gjedde A, et al. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: expression and action in brain. J Neurosci Res. 2015;93:1045–55.
Boitsova EB, Morgun AV, Osipova ED, Pozhilenkova EA, Martinova GP, Frolova OV, et al. The inhibitory effect of LPS on the expression of GPR81 lactate receptor in blood–brain barrier model in vitro. J Neuroinflamm. 2018;15:1–7.
Bergersen LH. Lactate transport and signaling in the brain: Potential therapeutic targets and roles in body-brain interaction. J Cereb Blood Flow Metab. 2015;35:176–85. https://doi.org/10.1038/jcbfm.2014.206.
Khilazheva ED, Pisareva NV, Morgun AV, Boitsova EB, Taranushenko TE, Frolova OV, et al. Activation of GPR81 lactate receptors stimulates mitochondrial biogenesis in cerebral microvessel endothelial cells. Ann Clin Exp Neurol. 2017;1:34–9.
Bravo CA, Vatner DE, Pachon R, Zhang J, Vatner SF. A food and drug administration-approved antiviral agent that inhibits adenylyl cyclase type 5 protects the ischemic heart even when administered after reperfusion. J Pharmacol Exp Ther. 2016;357:331–6.
Bers DM, Zaccolo M. Whole-cell cAMP and PKA activity are epiphenomena nanodomain signaling matters. Physiology. 2019;34:240–9.
Agarwal SR, Clancy CE, Harvey RD. Mechanisms restricting diffusion of intracellular camp. sci rep. 2016;6:1–11. https://doi.org/10.1038/srep19577.
Zaccolo M, De Giorgi F, Cho CY, Feng L, Knapp T, Negulescu PA, et al. A genetically encoded, flourescent indicator for cyclic AMP in living cells. Nat Cell Biol. 2000;2:25–9.
Ponsioen B, Zhao J, Riedl J, Zwartkruis F, van der Krogt G, Zaccolo M, et al. Detecting cAMP-induced Epac activation by fluorescence resonance energy transfer: Epac as a novel cAMP indicator. EMBO Rep. 2004;5:1176–80.
Agarwal SR, Fiore C, Miyashiro K, Ostrom RS, Harvey RD. Effect of adenylyl cyclase type 6 on localized production of cAMP by b-2 adrenoceptors in human airway smooth-muscle cells. J Pharmacol Exp Ther. 2019;370:104–10.
Agarwal SR, Miyashiro K, Latt H, Ostrom RS, Harvey RD. Compartmentalized cAMP responses to prostaglandin EP2 receptor activation in human airway smooth muscle cells. Br J Pharmacol. 2017;174:2784–96.
Grarup N, Moltke I, Andersen MK, Dalby M, Vitting-Seerup K, Kern T, et al. Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes. Nat Genet. 2018;50:172–4.
Acknowledgements
We thank the Yao lab for helpful discussions. The figures were made using BioRender.
Funding
This study was partially supported by National Institute of Health Grants (R01HL146574, RF1AG065345, R21AG073862 and R21AG064422) to YY.
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Devasani, K., Yao, Y. Expression and functions of adenylyl cyclases in the CNS. Fluids Barriers CNS 19, 23 (2022). https://doi.org/10.1186/s12987-022-00322-2
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DOI: https://doi.org/10.1186/s12987-022-00322-2
Keywords
- Adenylyl cyclases
- Blood–brain barrier
- CNS
- G-protein coupled receptors