Database for Annotation, Visualization and Integrated Discovery 2.1
National Institute of Allergy and Infectious Disease
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protein kinase cAMP-activated catalytic subunit alpha(PRKACA) protein kinase cAMP-activated catalytic subunit alpha(PRKACA) Related Genes Homo sapiens
CHROMOSOME 19,
CYTOBAND 19p13.1,
ENSEMBL_GENE_ID ENSG00000072062,
GENERIF_SUMMARY Protein kinase A enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein D in a hierarchical fashion., regulation of the membrane binding of PKCalpha, Katacalcin regulates human CD14+ PBMC migration via signaling events involving protein kinase A-dependent cAMP pathways., cAMP-induced inhibition of P-selectin expression is, in large part, mediated through activation of PKA., the effects of protein kinase A stimulation on sustained current in wild type and three disease-linked C-terminal mutant channels (D1790G, Y1795C, and Y1795H), Merlin was phosphorylated by PKA in cells in which PAK activity was suppressed, indicating that the two kinases function independently. PKA can phosphorylate merlin at serine 518, promoting heterodimerization between merlin and ezrin, Inhibition of PKCalpha markedly inhibited IP3-induced activation of calcium the current., PKACA is involved in extracellular (Ca2+) signalling mediated by the calcium sensing receptor., repressor nuclear factor-kappaB p50/p50 binding to DNA depends on phosphorylation of Ser337 by the protein kinase A catalytic subunit, Protein kinase A regulates caspase-9 activation by Apaf-1 downstream of cytochrome c, a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module is regulated by Protein Kinase A gating and then regulates invasion in breast cancer cell lines, claudin-3 phosphorylation by PKA may provide a mechanism for the disruption of tight junctions in ovarian cancer, A small but significant decrease in PKA, AKAP79, and PP2B in myometrial tissues from women in labor may contribute to a decrease in negative feedback on and enhancement of contractant signals at term, Protein kinase A-dependent phosphorylation of Lutheran/basal cell adhesion molecule glycoprotein regulates cell adhesion to laminin alpha5, GCMa acetylation is mediated by CBP, which stimulates GCMa transcriptional activity through cyclic AMP/protein kinase A signaling, CTP synthetase is phosphorylated by protein kinase A, kinase inhibits the phosphatidylinositiol (3,4,5)-trisphosphate and Gbetagamma-mediated regulation of its activity, Results imply a hindered transduction of the protein kinase A phosphorylation signal from cardiac troponin I to troponin C., analysis of a novel, noncanonical mechanism of modulation of beta-catenin signaling through direct phosphorylation of beta-catenin by PKA, promoting its interaction with CREB-binding protein, These observations suggest that in primary pulmonary fibroblasts, PKCalpha but not PKCdelta or PKCepsilon mediate the profibrotic effect of CCL18., ATP binding specifically to the ATPC site in S2- InsP3R-1 controls the susceptibility of the receptor to protein kinase A-mediated phosphorylation, Results suggest that gravin maintains a signaling complex that includes protein kinase A and phosphodiesterase 4D., transcriptomes associated with protein kinase A pathway was identified in human prostate cancer cells using Affymetrix GeneChip technology, Thus, PAR2 activates PKCepsilon and PKA in sensory neurons, and thereby sensitizes TRPV1 to cause thermal hyperalgesia., analysis of a novel mechanism for the phosphorylation of MYPT3 by PKA and activation of the catalytic activity through direct interaction of a central region of MYPT3 with its N-terminal region, Results suggest involvement of AMP-activated protein kinase in the control of expression of both metabolic genes, UCP3 and GLUT4, in the skeletal muscle of mice and of human newborns., STAT3 activation by G alpha(s) distinctively requires protein kinase A, JNK, and phosphatidylinositol 3-kinase, Data show that activation-dependent expression of matrix metalloproteinases in peripheral blood mononuclear cells involves protein kinase A., activation of RankL gene expression by PKA- and gp130-inducers is mediated via common regulatory domains that also served to facilitate the activity of 1,25-(OH)2D3, Rap1 mediates cyclic AMP-stimulated neurotensin secretion downstream of both Epac and protein kinase A signaling pathways, Opposite roles for the protein kinase A transgene are defined in the formation of initial memories and extinction memories, representing the first genetic evidence that protein kinases may be constraints for the extinction of fear., LXRalpha is regulated not only by oxysterol derivatives but also by PKA-mediated phosphorylation, which suggests that nutritional regulation of SREBP-1c and lipogenesis could be regulated at least partially through modulation of LXR, These results indicate that the reactive oxygen species-mediated TNF-alpha-induced IL-8 transcription is regulated by NF-kappaB/RelA phosphorylation at the critical Ser(276) residue by PKAc, resulting in stable enhanceosome formation on target genes., STAT-3 activation by DFMO is at least in part mediated through the PKA pathway, PTH induces an increased activity of the eNOS system through PKA and PKC pathways, Protein phosphorylation by PRKACA at Ser(637) results in clear alterations in Drp1 function and mitochondrial morphology., cyclic AMP-dependent protein kinase regulates proteasome function through phosphorylation of Rpt6, The anx 2-S100A10/CFTR complex is important for CFTR function across epithelia., Nuclear PKA C subunit co-locates with HA95 in splicing factor compartments and regulates pre-mRNA splicing, possibly through a cAMP-independent mechanism., PKA and VEGFR2 converge at the MEK/ERK1/2 pathway to protect serum starved neuronal cells from a caspase-dependent cell death., PKA-dependent phosphorylation enhances the response of RyR2 to luminal Ca(2+) and reduces the threshold for SOICR and this effect of PKA is largely mediated by phosphorylation at Ser-2,030, Contrary to the classical model of PKA activation, elevated cAMP does not allow RIalpha and Calpha to diffuse far apart unless the pseudosubstrate inhibitor PKI or locally concentrated substrate is coexpressed, Prostaglandin E2 activates HPK1 kinase activity via a PKA-dependent pathway, Protein kinase A, not Epac, suppresses hedgehog activity and regulates glucocorticoid sensitivity in acute lymphoblastic leukemia cells, In patients with Alzheimer disease, over-activation of calpain because of calcium dysregulation causes increased degradation and thus decreased activity of PKA,which, in turn, contributes to down-regulation of CREB and impaired cognition and memory., Vitamin K(2) modulates its target gene expression in osteoblastic cells through the PKA-dependent mechanism., This study demonstrates that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase A (PKAc) is essential for NF-kappaB DNA binding and transactivation activity., Data suggest that PKA effects on IFNT regulation might be mediated through CBP/p300 coactivation, particularly as CBP and Ets2 occupy the proximal promoter region of IFNT in bovine trophoblast CT-1 cells., These results suggest a novel mechanism of ANP protective effects against agonist-induced pulmonary endothelial cell barrier dysfunction via inhibition of Rho signaling by Epac/Rap1-Rac and PKA signaling cascades., analysis of allosteric cooperativity in protein kinase A, The results herein provide initial evidence that the inhibitory effect of hypoxia on MMP-9 by mature dendritic cells requires the activation of A(2b) in a cAMP/PKA-dependent pathway., Data provide the first evidence that 17beta-estradiol can inhibit PKA overactivation and PKA-induced tau hyperphosphorylation, implying a preventive role of 17beta-estradiol in AD-like tau pathology., The selective use of PKA and Epac-1 pathways to inhibit distinct aspects of fibroblast activation illustrate the pleiotropic ability of PGE(2) to inhibit diverse fibroblast functions., A switch to type II PKA activity is not necessary for increased kinase activity or tumorigenesis., Androgen actively evokes a nongenomic signaling pathway to activate PKA that is needed for the genomic functioning of nuclear androgen receptor., activation of protein kinase A elicits an immediate response through induction of genes such as ID2 and FosB, followed by sustained secretion of bone-related cytokines such as BMP-2, IGF-1, and IL-11, growth factor signals promote phosphorylation of ER coactivator PELP1 via PKA pathway, and such modification may have functional implications in breast tumors with deregulated growth factor signaling, The distribution of DNA-PK between nuclear and cytoplasmic compartments can thus potentially be influenced by relative inputs of cAMP signaling through the EPAC and PKA pathways., HPV16 E7-dependent transformation activates NHE1 through a PKA-RhoA-induced inhibition of p38alpha., PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650, Data show that PKC activation resulted in redistribution of gravin and PKA constructs to the same subcellular site, and suggest that this response to PKC activity may mediate PKC dependent control of PKA activity., cAMP/PKA signaling enhances ERRalpha phosphorylation and nuclear localization, recruitment to the SP-A promoter, and interaction with PKAcat and SRC-2, resulting in the up-regulation of SP-A gene transcription., catalytic subunits level of PKA inhibit angiogenesis, In human primary pigmented nodular adrenocortical disease tissues, dexamethasone paradoxically stimulates cortisol release through a glucocorticoid receptor-mediated effect on PKA catalytic subunits., In PKA the ligand selectivity is controlled mainly at the level of ligand affinity., Findings show that PKIB and PKA-C kinase can have critical functions of aggressive phenotype of PCs through Akt phosphorylation and that they should be a promising molecular target for PC treatment., Report expression of protein kinase A and C subunits in post-mortem prefrontal cortex from persons with major depression and normal controls., Activation of TR4 orphan nuclear receptor gene promoter by cAMP/PKA and C/EBP signaling., Data suggest that the state of tau3 phosphorylation by protein kinase A affects the mode of 14-3-3zeta binding and by this means might modify tau filament formation., Lfc is a phosphorylated protein and demonstrate that 14-3-3 interacts directly and in a phosphorylation-dependent manner with Lfc., CD9 increases GCM1 expression via the cAMP/PKA signaling pathway, resulting in the increase in ERVWE1 expression., Results suggest that PKA can negatively regulate ERalpha, at least in part, through FoxH1., hepatic serum amyloid A expression is enhanced via protein kinase A-dependent mechanism, NF-kappaB p65 (Ser276) phosphorylation by PKA promotes the malignant phenotype and holds potential as a therapeutic target in HNSCC., Findings demonstrate that interactions between endogenous RSK1 and PKAc in intact cells regulate the ability of cAMP to activate PKA and identify a novel mechanism by which PKA activity is regulated by the Erk1/2 pathway., Protein kinase A activation confers resistance to trastuzumab in human breast cancer cell lines, These results highlight serines 11 and 92 as new players in Snail1 regulation and suggest the participation of CK2 and PKA in the modulation of Snail1 functionality., These results indicate that high glucose can increase adipogenic and inhibit osteogenic differentiation by activating cAMP/PKA/ERK pathway in MG-63 cells., Data show that Phosphorylation of The(197) in the activation loop on protein kinase A decreased the K(m) by approximately 15- and 7-fold for kemptide and ATP, respectively., These data demonstrate that PKA phosphorylation of Kv4.2 plays an important role in the trafficking of Kv4.2 through its specific interaction with KChIP4a., OATP2B1/SLCO2B1 function is modulated by protein kinase C-mediated internalization, analysis of evolutionary conserved residues that are crucial for the catalytic activity of PKA and Pak2, Thrombin and collagen induce a feedback inhibitory signaling pathway in platelets involving dissociation of the catalytic subunit of protein kinase A from an NFkappaB-IkappaB complex, cAMP induces leptin expression in placental cells and that this effect seems to be mediated by a cross talk between PKA and MAPK signaling pathways., Data hypothesize that VEGFR-2 forms a signaling complex with S1P(1) and and protein kinase C-alpha , evoking bidirectional signaling regulating both ERK1/2 phosphorylation and haptotaxis of ML-1 cells., These data reveal a new role for TSP-1 in promoting platelet aggregation through modulation of the cAMP-PKA signaling pathway., Findings identify HDAC5 as a substrate of PKA and reveal a cAMP/PKA-dependent pathway that controls HDAC5 nucleocytoplasmic shuttling and represses gene transcription., The crystal structures demonstrate that, in accord with the previously reported bisubstrate character of adenosine analogue-oligoarginine conjugates, the inhibitors occupy both binding sites of the catalytic subunit alpha of cAMP-dependent protein kinase., This review discusses the different characteristics of regulating the activity and subcellular localization of MK5 and RSK1 by PKA and the functional implications of these interactions., The present study delineates the fundamental elements of a core promoter structure that will be helpful for future studies regarding the regulation of RAB25 gene., Findings of PKA regulation of HSF1 through S320 phosphorylation show the signaling networks converging on this factor and may contribute to elucidating its complex roles in the stress response and understanding HSF1 dysregulation in disease., Findings show a connection between PKA activity and GJIC mediated by PI3K-independent mechanisms., ciliary localization of Sufu is dependent on ciliary-localized Gli proteins, and is inhibited by PKA activation, cAMP-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both K(2P)3.1 and K(2P)9.1, down-regulation of PKA dysregulates the alternative splicing of tau exon 10 and contributes to neurofibrillary degeneration in Alzheimer disease by causing an imbalance in 3R-tau and 4R-tau expression, The results revealed that, in SGC-7901 cells, soluble fibronectin increased RhoA activity and blocked the inhibition of RhoA activity by cAMP/PKA., The regulation of RORalpha activity by PKA as well as CaMK-IV provides a new link in the signalling network that regulates metabolic processes such as glycogen and lipid metabolism., Protein kinase A activity at the endoplasmic reticulum surface is responsible for augmentation of human ether-a-go-go-related gene product (HERG), analysis of a novel TGFbeta/PKA tumor suppressor pathway that acts directly on a known cell survival mechanism that responds to stress with the survivin/XIAP dependent inhibition of caspases that effect apoptosis, N-terminal sequence encoded by alternative use of exons upstream of exon 2 in the PRKACA gene does not influence C subunit activities such as holoenzyme formation, cAMP sensitivity, Occlusion of PKA-dependent processes is one of the molecular mechanisms underlying cognitive decline in Huntington disease., Data show that protein kinase A (PKA) regulates the alternative splicing of Ca(2)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) to produce variants that differentially modulate neuronal differentiation., Abnormality in beta-adrenergic-PKA signaling may contribute to cardiomyopathy and heart failure through dysregulation in the alternative splicing of CaMKIIdelta exons 14, 15, and 16 and up-regulation of CaMKIIdeltaC., Results show that induction of RhoE by cAMP is mediated through protein kinase A (PKA) and promotes BeWo cell fusion but has no effect on functional differentiation., A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration., Cigarette smoke extract decreased Epac1 expression, but did not affect Epac2 and PKA expression., Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling, Data show that protein kinase A (PKA) phosphorylation has a drastic impact on Na(+)/K(+)-ATPase (NKA) structure and dynamics., The protein kinase A pathway enhance ipopolysaccharide-induced IL-6, IL-8, and prostaglandin Eproduction by human gingival fibroblasts., Activation of protein kinase A and exchange protein directly activated by cAMP promotes adipocyte differentiation of human mesenchymal stem cells, Findings indicate that Calpha2 through the hydrophobic pocket has the ability to bind intracellular targets in the sperm cell, which may modulate protein stability, activity and/or cellular localization., Data indicate that an increase in cAMP/PKA activity resulted in the dissociation of SIRT1 and DBC1 in an AMP-activated protein kinase (AMPK)-dependent manner., Data show that the cAMP/PKA/CREB signaling pathway initiates acidosis-induced V-ATPase trafficking in salivary ducts via regulation of Rab11b expression., The effect of norepinephrine on amyloid beta(1-42) peptide-induced responses in migroglia-like THP-1 cells is contingent on cyclic AMP/PKA pathways and cAMP responsive element binding protein (CREB) activation., genistein may play a beneficial role in vascular function through targeting the PKA/CREB/eNOS/NO signaling pathway, In prostate cancer cells, S100A8 expression is stimulated by prostaglandin E2 via EP2 and EP4 receptors through activation of the protein kinase A signaling pathway and stimulation of CCAAT/enhancer-binding-protein-beta binding to the S100A8 promoter., Glucagon-like peptide-1 inhibits angiotensin II-induced mesangial cell damage via protein kinase A, PKA-phosphodiesterase(PDE)4D3-A kinase anchor protein (AKAP)9 complex generates spatial compartmentalization of cyclic adenosine monophosphate (cAMP) signaling at the centrosome., High CB1 and PKA expression is associated with low survival intracellular pathway activation and high iNOS activation in ischemic heart disease patients., Data show that TIMP-2-mediated inhibition of vascular endothelial cell permeability involves an integrin alpha3beta1-Shp-1-cAMP/protein kinase A-dependent vascular endothelial cadherin cytoskeletal association., We conclude that the effects of selenoprotein H on mitochondrial biogenesis and mitochondrial function are probably mediated through protein kinase A-CREB-PGC-1alpha and Akt/protein kinase B-CREB-PGC-1alpha pathways., Data indicate inhibition of cAMP-dependent protein kinase A with H89 partially reverted resistance of NB4.437r cells to ST1926., Data suggest that cross-talk occurs between cAMP/PKA and the IL-2R beta/Jak3/Stat5b cascade in T-cells., the PKA pathway is functionally linked to androgen receptor in the progression of prostate cancer, PKA is a regulator of MYC; its different catalytic subunits have distinct biologcial roles, the inhibitory effect of cAMP on migration, ruffling, focal adhesion dynamics and paxillin localisation is mediated by PKA, whilst EPAC potentiates migration., Comparative analysis of the binding responses of mutations to mAKAP could provide important information about how these mutations modulate PKA and PDE4D3 signaling., while there is no change in type II regulatory (RIIalpha) or catalytic (Calpha) subunit expression, site specific RIIalpha (Ser96) and Calpha (Thr197) phosphorylation are increased in heart failure, as well as expression of type I regulatory subunit (RI), This study is the first to demonstrate subversion of host cAMP-dependent protein kinase activity by the intracellular bacterial pathogen Coxiella burnetii to prevent apoptosis and survive within macrophages., Activation of PKA catalytic subunits promoted splicing factor SC35-mediated tau exon 10 inclusion., Data show that cAMP/alpha isoform of the catalytic subunit of human PKA (PKAc-alpha) signaling can disrupt microtubule (MT) cytoskeleton by the phosphorylation of microtubule-Associated Protein 4 (MAP4)., Interleukin 33 has a role in enhancing the p38 MAPK and PKA signaling pathways in melanocytes, These results indicate that HIV-1-associated PKA is required for early reverse transcription of the retroviral genome both in cell free intact viruses and in target cells., These results show involvement of PKA, CREB and PGC-1alpha in the regulation of OXPHOS in cell transition from the replicating to the quiescent state., Genetic alterations of the catalytic subunit of PKA were found to be associated with bilateral adrenal hyperplasias and unilateral cortisol-producing adrenal adenomas., Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the FL-HCCs examined (15/15) suggests that this genetic alteration contributes to tumor pathogenesis., visfatin modulates glucose production in HepG2 cells through the PKA/CREB pathway, rather than via SIRT1 signaling., this study identified a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of cortisol-producing adrenocortical adenomas (ACAs) and validated in 65.5% of a total of 87 ACAs., These results demonstrate that glucagon increases hepatic FGF21 secretion via a posttranscriptional mechanism and provide evidence that both the PKA branch and EPAC branch of the cAMP pathway play a role in mediating this effect., recurrent gain-of-function mutation in PRKACA in cortisol-producing adrenal adenomas, AKAP 149-PKA-PDE4A complex localization is related with YTX effect in K-562 cell line, The L206R PRKACA mutant abolished its binding to the regulatory subunit of (cAMP)-dependent protein kinase (PKA) (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation in corticotropin-independent Cushing's syndrome., this study discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy., KCNE1 distal C-terminus appears essential for the regulation of yotiao-mediated PKA phosphorylation., These data confirm and extend previous observations that somatic PRKACA mutations are specific for adrenocortical adenomas causing Cushing's syndrome., Of the 13 patients with Cortisol Producing Adenomas who showed overt Cushing's syndrome, 3 (23%) had recurrent somatic mutations of the PRKACA gene, p.L206R (c.617 T>G), and there were no mutations in subclinical Cushing's syndrome., PKA phosphorylation of CREB was involved in the EP4 receptor-mediated PGE2 upregulation of c-Myc in hepatocellular carcinoma., PKA compartmentalization via AKAP220 and AKAP12 contributes to endothelial barrier regulation., Its signaling pathway is associated with the progression and prognosis of colorectal neoplasms., It is unlikely that mutation at PRKACA locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway cannot be ruled out., Case Reports, Leu206Arg and Leu199_Cys200insTrp mutations in PRKACA impair its association with PRKAR2B and PRKAR1A., In this cohort of fibrolamellar hepatocellular carcinoma, almost 80% contained the DNAJB1-PRKACA fusion transcript., Data show that silencing ezrin-radixin-moesin (ERM) protein expression ablates deleted in colorectal carcinoma protein (DCC)-protein kinase A (PKA) interaction and specifically blocks netrin-induced PKA activity and phosphorylation., These findings suggest that C18orf42 may be a novel PKA signaling gene that serves as an endogenous disruptor peptide for PKA-AKAP interactions., PRKACAL206R is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion., analysis of how the conformational dynamics of protein kinase A induced by a lethal mutant of phospholamban hinder phosphorylation, association of ezrin with the actin cytoskeleton and phosphorylation on Thr567 are required, but not sufficient, for PKA and EPAC1 to synergistically promote cell spreading following elevations in intracellular cAMP., ITM2A expression is positively regulated by PKA-CREB signaling and ITM2A expression interferes with autophagic flux by interacting with vacuolar ATPase., Kapbeta2 interacts with ULK2 through ULK2's putative PY-NLS motif, and facilitates transport from the cytoplasm to the nucleus, depending on its Ser1027 residue phosphorylation by PKA, thereby reducing autophagic activity., Protein kinase A activity is necessary for fission and fusion of Golgi to endoplasmic reticulum retrograde tubules., Data indicate that protein kinase A (PKA) phosphorylates only serine-253 amino acid on activator of G-protein signaling 1 protein Dexras1 (RASD1)., PKA phosphorylates the ATPase inhibitory factor 1 and inactivates its capacity to bind and inhibit the mitochondrial H(+)-ATP synthase., Akt and PKA phosphorylated KLHL3 at S433, and phosphorylation of KLHL3 by PKA inhibited WNK4 degradation., DNAJB1-PRKACA was evaluated as a key driver of fibrolamellar carcinoma and as a candidate therapeutic target, Data show that activated PKA phosphorylates the 19S subunit, Rpn6/PSMD11 (regulatory particle non-ATPase 6/proteasome subunit D11) at Ser14., No somatic mutations were observed in PRKACA in a cohort of GH-secreting pituitary adenomas., Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment.,
OMIM_DISEASE Cushing syndrome, ACTH-independent adrenal, somatic,
SP_COMMENT catalytic activity:ATP + a protein = ADP + a phosphoprotein., enzyme regulation:Activated by cAMP., function:Phosphorylates a large number of substrates in the cytoplasm and the nucleus., PTM:Asn-3 is partially deaminated to Asp giving rise to 2 major isoelectric variants, called CB and CA respectively., similarity:Belongs to the protein kinase superfamily., similarity:Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily., similarity:Contains 1 AGC-kinase C-terminal domain., similarity:Contains 1 protein kinase domain., subcellular location:Translocates into the nucleus (monomeric catalytic subunit) (By similarity). The inactive holoenzyme is found in the cytoplasm., subunit:A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits., tissue specificity:Isoform 2 is sperm specific.,