Dynamic integration of alpha-adrenergic and cholinergic signals in the atria: role of G protein-regulated inwardly rectifying K+ channels.
Numerous heptahelical receptors use activation of heterotrimeric G proteins to convey a multitude of extracellular signals to appropriate effector molecules in the cell. Both high specificity and correct integration of these signals are required for reliable cell function. Yet the molecular machineries that allow each cell to merge information flowing across different receptors are not well understood. Here we demonstrate that G protein-regulated inwardly rectifying K(+) (GIRK) channels can operate as dynamic integrators of alpha-adrenergic and cholinergic signals in atrial myocytes. Acting at the last step of the cholinergic signaling cascade, these channels are activated by direct interactions with betagamma subunits of the inhibitory G proteins (G betagamma), and efficiently translate M(2) muscarinic acetylcholine receptor (M2R) activation into membrane hyperpolarization. The parallel activation of alpha-adrenergic receptors imposed a distinctive "signature" on the function of M2R-activated GIRK1/4 channels, affecting both the probability of G betagamma binding to the channel and its desensitization. This modulation of channel function was correlated with a parallel depletion of G beta and protein phosphatase 1 from the oligomeric GIRK1 complexes. Such plasticity of the immediate GIRK signaling environment suggests that multireceptor integration involves large protein networks undergoing dynamic changes upon receptor activation.
Nikolov
Emil N
EN
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834.
Ivanova-Nikolova
Tatyana T
TT
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834. Electronic address: ivanovanikolovat@ecu.edu.
D000818:Animals; D016275:Atrial Function / Q000502:physiology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054645:Protein Phosphatase 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D043585:Receptor, Muscarinic M2; D011942:Receptors, Adrenergic, alpha; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D019204:GTP-Binding Proteins