Dynamic Integration of α-Adrenergic and Cholinergic Signals in the Atria

Abstract

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 ␣-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 ␤␥ subunits of the inhibitory G proteins (G␤␥), and efficiently translate M 2 muscarinic acetylcholine receptor (M2R) activation into membrane hyperpolarization. The parallel activation of ␣-adrenergic receptors imposed a distinctive "signature" on the function of M2R-activated GIRK1/4 channels, affecting both the probability of G␤␥ binding to the channel and its desensitization. This modulation of channel function was correlated with a parallel depletion of G␤ 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.The heart functions in a continuously changing environment responding to excitatory and inhibitory signals from the sympathetic and parasympathetic branches of autonomic nervous system. Both branches use members of the large family of seven transmembrane G protein-coupled receptors (GPCRs) 2 as membrane gateways for their opposing signals. At rest, parasympathetic signals reduce the heart rate through activation of G i/o -coupled M2Rs. During exercise and stress, sympathetically derived catecholamines target coexisting ARs and increase the cardiac output by accelerating the heart rate and enhancing contractility. The ␤ 1 -, ␤ 2 -, and ␣ 1 -ARs are the most predominant AR subtypes in cardiac myocytes (1). These receptors activate different signaling cascades with ␣ 1 -ARs coupling to G q , ␤ 1 -ARs coupling to G s , and ␤ 2 -ARs coupling to both G s and G i pathways. Although the cellular processes triggered upon activation of individual adrenergic and M 2 receptors have been well delineated (1), how cardiac myocytes integrate the inhibitory and excitatory signals transmitted by these receptors remains less well understood. Signal integration might arise from heterodimerization of members of distinct subfamilies of GPCRs. Such receptor heterodimerization expands the operational features of the receptors involved, modulating either receptor trafficking or function (2). Importantly, heterodimerization of ␤ 1 -and ␤ 2 -ARs in intact cardiac myocytes was recently reported to give rise to a new population of ␤-ARs with enhanced signaling properties (3).Assembly of receptor heterodimers, however, is perhaps only one of the diver...

G Protein–Dependent and G Protein–Independent Signaling Pathways and Their Impact on Cardiac Function

“…Also, via a Gβγ-dependent mechanism, both M 2 R and S1P 1 R have been demonstrated in atrial and ventricular myocytes to increase the open probability of the K + channel I K Ach , promoting membrane hyperpolarization to decrease the action potential duration, thereby decreasing chronotropy and inotropy (Fig. 1) 31, 47 . Via a Gγ-like domain, RGS6 has been shown to interact specifically with Gβ 5 48 and a recent study reported that this complex binds to and promotes the deactivation of I K Ach , thereby modulating M 2 R-mediated effects on myocyte current kinetics 49 .…”