id: PW:0000543 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000543 title: protein kinase a (pka) signaling pathway description_xrefs: - GO:0010737 description: Protein kinase A (PKA) signaling is a widely used intracellular pathway and the major route for channeling the second messenger cAMP signal. Ligand activated G-protein coupled receptors that transduce the signal via the Gs alpha subunit of the heterotrimeric G protein lead to activation of the adenylyl cyclase enzymes (AC) that catalyze the formation of cAMP from ATP. GTP-bound Gs binds to AC and increases the affinity between the C1 and C2 cytoplasmic domains whose interface constitutes the ATP binding site. Nine membrane-bound and one soluble adenylyl cyclase have been so far identified. Most tissues express more than one AC and almost every AC is expressed in the brain. cAMP binding to the PKA complex leads to dissociation of the catalytic subunits from the holoenzyme. In the inactive state, the holoenzyme consists of two catalytic subunits (C) bound noncovalently to a regulatory dimer (RI or RII). There are two type I and two type II regulatory subunits and three catalytic subunits in humans; rodents express only two catalytic subunits. Each regulatory subunit has two cAMP binding sites; type I has a higher affinity for cAMP than type II. Binding of four molecules of cAMP to the regulatory dimer induces a conformational change that leads to dissociation of the holoenzyme and release of the catalytic monomers. cAMP is hydrolyzed by phosphodiesterases (PDE), the only enzymes degrading cycling nucleotides. The 21 mammalian genes are subdivided in 11 families based on kinetic and pharmacological properties. Of these, 3 families are specific for cAMP, 3 other for cGMP and 5 hydrolyze both. PDEs not only contribute to the regulation of cAMP concentration but also modulate the duration and extent of cAMP signaling, and thus of PKA. The compartmentalization of PKA is mediated by the AKAP family of scaffold proteins ( A K inase A nchoring P rotein). AKAPs bring together PKA (and other kinases) along with phosphatases and phosphodiesterases, in some cases AC and target proteins to fine tune the many outcomes of PKA signaling. 14 Akap genes in mammals give rise to more than 50 proteins. Primarily they target the regulatory type II subunits; a few possess dual specificity and bind both subunits types. The various combinations of AKAP-PKA allow for the diversity of cellular and tissue distribution of the serine/threonine PKA complexes and the modulation of their function and underlie the extensive use of this intracellular pathway. PKA cross-talks or integrates with other signaling pathways. The PKA signaling pathway has been implicated in many cellular and physiological processes, from metabolism and reproduction, to cardiac function, memory and learning. diagram_image: https://rgd.mcw.edu/pathway/PW0000543/protein%20kinase%20A%20(PKA)%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000543/protein%20kinase%20A%20(PKA)%20signaling%20pathway/protein%20kinase%20A%20(PKA)%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000227 label: G protein mediated signaling pathway via Galphas family diagram_gene_links: - id: RGD:2319682 label: Gnas diagram_chemicals: - id: CHEBI:15422 label: ATP - id: CHEBI:17489 label: cAMP diagram_edges: - source: ATP relation: positively_affects target: cAMP - source: Gnas relation: associated_with target: GPCRs upstream PKA - source: Pdes relation: negatively_affects target: cAMP - source: Pka complex relation: positively_affects target: cardiovascular function - source: Pka complex relation: positively_affects target: cytoskeleton dynamics - source: Pka complex relation: positively_affects target: exocytosis - source: Pka complex relation: positively_affects target: gene expression - source: Pka complex relation: positively_affects target: metabolism - source: Pka complex relation: positively_affects target: nuclear dynamics - source: Pka complex relation: positively_affects target: regulation of ion channels - source: Pka complex relation: positively_affects target: regulation of neuroreceptors diagram_labels: - cAMP --+> Pka complex - cardiovascular function - cytoskeleton dynamics - exocytosis - gene expression - Gnas --+> AC members - metabolism - nuclear dynamics - regulation of ion channels - regulation of neuroreceptors diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/adenylate-cyclase-members label: AC members - href: /wg/home/pathway2/molecular-pathways2/akap-members label: Akaps - href: /wg/home/pathway2/molecular-pathways2/phosphodiesterase-members label: Pdes - href: /wg/home/pathway2/molecular-pathways2/protein-kinase-a-complex label: Pka complex - href: /wg/home/pathway2/molecular-pathways2/upstream-pathways-activating-pka-intracellular-signaling label: GPCRs upstream PKA references: - id: RGD:2312469 citation: Sadana R and Dessauer CW, Neurosignals. 2009;17(1):5-22. Epub 2008 Oct 24. - id: RGD:2312475 citation: Tasken K and Aandahl EM, Physiol Rev. 2004 Jan;84(1):137-67. - id: RGD:2312477 citation: Carnegie GK, etal., IUBMB Life. 2009 Apr;61(4):394-406. - id: RGD:2312479 citation: Conti M and Beavo J, Annu Rev Biochem. 2007;76:481-511. - id: RGD:5129742 citation: Hanoune J and Defer N, Annu Rev Pharmacol Toxicol. 2001;41:145-74. - id: RGD:5129744 citation: Patel TB, etal., Gene. 2001 May 16;269(1-2):13-25. - id: RGD:5129745 citation: Mayr B and Montminy M, Nat Rev Mol Cell Biol. 2001 Aug;2(8):599-609. - id: RGD:5129829 citation: Taylor SS, etal., Biochim Biophys Acta. 2005 Dec 30;1754(1-2):25-37. Epub 2005 Sep 22. - id: RGD:5129845 citation: Zaccolo M Eur J Cell Biol. 2006 Jul;85(7):693-7. Epub 2006 Feb 7. - id: RGD:5129876 citation: Scott JD Biochem Soc Trans. 2006 Aug;34(Pt 4):465-7. - id: RGD:5129914 citation: Beene DL and Scott JD, Curr Opin Cell Biol. 2007 Apr;19(2):192-8. Epub 2007 Feb 20. - id: RGD:5129951 citation: Sands WA and Palmer TM, Cell Signal. 2008 Mar;20(3):460-6. Epub 2007 Oct 12. - id: RGD:5129985 citation: Abel T and Nguyen PV, Prog Brain Res. 2008;169:97-115. - id: RGD:5129997 citation: Murray AJ Sci Signal. 2008 Jun 3;1(22):re4. - id: RGD:5130056 citation: Baillie GS FEBS J. 2009 Apr;276(7):1790-9. Epub 2009 Feb 23. - id: RGD:5130066 citation: Mauban JR, etal., Physiology (Bethesda). 2009 Apr;24:78-87.