Coordination of membrane excitability through a GIRK1 signaling complex in the atria.
Control of heart rate is a complex process that integrates the function of multiple G protein-coupled receptors and ion channels. Among them, the G protein-regulated inwardly rectifying K+ (GIRK or KACh) channels of sinoatrial node and atria play a major role in beat-to-beat regulation of the heart rate. The atrial KACh channels are heterotetrameric proteins that consist of two pore-forming subunits, GIRK1 and GIRK4. Following m2-muscarinic acetylcholine receptor (M2R) stimulation, KACh channel activation is conferred by the direct binding of G protein betagamma subunits (Gbetagamma) to the channel. Here we show that atrial KACh channels are assembled in a signaling complex with Gbetagamma, G protein-coupled receptor kinase, cyclic adenosine monophosphate-dependent protein kinase, two protein phosphatases, PP1 and PP2A, receptor for activated C kinase 1, and actin. This complex would enable the KACh channels to rapidly integrate beta-adrenergic and M2R signaling in the membrane, and it provides insight into general principles governing spatial integration of different transduction pathways. Furthermore, the same complex might recruit protein kinase C (PKC) to the KACh channel following alpha-adrenergic receptor stimulation. Our electro-physiological recordings from single atrial KACh channels revealed a potent inhibition of Gbetagamma-induced channel activity by PKC, thus validating the physiological significance of the observed complex as interconnecting site where signaling molecules congregate to execute a coordinated control of membrane excitability.
Nikolov
Emil N
EN
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA.
Ivanova-Nikolova
Tatyana T
TT
D000818:Animals; D016275:Atrial Function / Q000502:physiology; D002462:Cell Membrane / Q000502:physiology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006325:Heart Atria / Q000166:cytology; D006339:Heart Rate; D015640:Ion Channel Gating; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D043585:Receptor, Muscarinic M2 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D043585:Receptor, Muscarinic M2; D011493:Protein Kinase C