AKAP79, PKC, PKA and PDE4 participate in a Gq-linked muscarinic receptor and adenylate cyclase 2 cAMP signalling complex

Biochem J. 2013 Oct 1;455(1):47-56. doi: 10.1042/BJ20130359.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism*
  • Acetylcholine / metabolism
  • Adenylyl Cyclases / genetics
  • Adenylyl Cyclases / metabolism*
  • Animals
  • Calcineurin / genetics
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Rats
  • Receptor, Muscarinic M3 / genetics
  • Receptor, Muscarinic M3 / metabolism*
  • Signal Transduction
  • Single-Cell Analysis
  • Transfection

Substances

  • A Kinase Anchor Proteins
  • AKAP5 protein, human
  • Receptor, Muscarinic M3
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Calcineurin
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Adenylyl Cyclases
  • adenylyl cyclase 2
  • Acetylcholine
  • Calcium