title: AKAP79, PKC, PKA and PDE4 participate in a Gq-linked muscarinic receptor and adenylate cyclase 2 cAMP signalling complex.
abstract: AC2 (adenylate cyclase 2) is stimulated by activation of Gq-coupled muscarinic receptors through PKC (protein kinase C) to generate localized cAMP in HEK (human embryonic kidney)-293 cells. In the present study, we utilized a sensitive live-cell imaging technique to unravel the proteins that play essential roles in a Gq-coupled muscarinic receptor-mediated cAMP signalling complex. We reveal that, upon agonist binding to the Gq-coupled muscarinic receptor, AKAP79 (A-kinase-anchoring protein 79) recruits PKC to activate AC2 to produce cAMP. The cAMP formed is degraded by PDE4 (phosphodiesterase 4) activated by an AKAP-anchored PKA (protein kinase A). Calcineurin, a phosphatase bound to AKAP79, is not involved in this regulation. Overall, a transient cAMP increase is generated from AC2 by Gq-coupled muscarinic receptor activation, subject to sophisticated regulation through AKAP79, PKC, PDE4 and PKA, which significantly enhances acetylcholine-mediated signalling.
authors.affiliation: *Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
authors.forename: Jia X
authors.initials: JX
authors.lastname: Shen
authors.forename: Dermot M F
authors.initials: DM
authors.lastname: Cooper
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000109:Acetylcholine / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059010:Single-Cell Analysis; D014162:Transfection
chemical_list: D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; D043587:Receptor, Muscarinic M3; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019703:Calcineurin; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000262:Adenylyl Cyclases; C100622:adenylyl cyclase 2; D000109:Acetylcholine; D002118:Calcium
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