Adjustments to cardiac output are made on a beat-to-beat basis in response to internal and external stimuli, and are mediated by the changing balance of input from the sympathetic and parasympathetic branches of the autonomic nervous system. While parasympathetic input normally tempers the pro-arrhythmic influence of sympathetic activation, too much parasympathetic influence can predispose to atrio-ventricular block or atrial fibrillation (a key risk factor for stroke). Conversely, too little parasympathetic influence is associated with heart failure, and is an independent predictor of increased morbidity and mortality in patients with coronary artery or congenital heart disease, and following myocardial infarction. Collectively, these observations suggest that altered parasympathetic regulation of the heart likely contributes to a broad spectrum of cardiac dysfunction, while simultaneously highlighting the inherent therapeutic promise of manipulations designed to predictably alter parasympathetic tone in the heart. The premise of this project is that the diagnostic and therapeutic potential associated with the parasympathetic regulation of the heart cannot be fully-realized without a clearer understanding of the signaling pathway(s) mediating its influence. A critical signaling pathway mediating the parasympathetic influence on the heart consists of the type 2 muscarinic acetylcholine receptor (M2R) and the G protein-gated potassium channel IKACh; the M2R-IKACh signaling pathway is a major determinant of cardiac rhythmicity, and dysregulation of this pathway has been implicated in both atrial and ventricular arrhythmias. Work in the initial project period established that the RGS6/G5 complex accounts for much of the RGS- dependent negative modulation of the M2R-IKACh signaling pathway, and that loss of this inhibitory influence yields enhanced parasympathetic signaling in the heart. The goals for the next project period are articulated in two Specific AIMs that are designed to: (1) Identify molecules and mechanisms underlying the RGS modulation of parasympathetic signaling, and (2) Develop targeted approaches to manipulate parasympathetic signaling in the heart. The proposed studies employ innovative and complementary approaches that leverage the unique strengths and reagents of two research labs, along with the expertise of an extended group of collaborators with overlapping research interests. Successful completion of the proposed work will yield a detailed understanding of the RGS-dependent modulation of parasympathetic signaling in the heart, along with tangible insights into the therapeutic potential associated with direct pharmacologic manipulation of the IKACh channel. Collectively, these efforts will result in a sophisticated understanding of the molecular and cellular mechanisms that shape the parasympathetic regulation of the heart, knowledge that can be translated into improved diagnostic and therapeutic approaches for arrhythmias.
Normal heart function requires a healthy balance between excitatory and inhibitory signals provided by the nervous system. Imbalance in this critical regulatory system can trigger arrhythmias, often with fatal consequences. The work proposed in this application will yield a clearer understanding of the molecular and genetic factors that impact the regulation of the heart by the nervous system, and the knowledge gained will facilitate the rational design of interventions aimed at better diagnosis, treatment, and prevention of arrhythmia.
|Lee, Steven W; Anderson, Allison; Guzman, Pilar A et al. (2018) Atrial GIRK Channels Mediate the Effects of Vagus Nerve Stimulation on Heart Rate Dynamics and Arrhythmogenesis. Front Physiol 9:943|
|Kulkarni, Kanchan; Xie, Xueyi; Marron Fernandez de Velasco, Ezequiel et al. (2018) The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. PLoS One 13:e0193798|
|Anderson, Allison; Kulkarni, Kanchan; Marron Fernandez de Velasco, Ezequiel et al. (2018) Expression and relevance of the G protein-gated K+ channel in the mouse ventricle. Sci Rep 8:1192|
|Mesirca, Pietro; Bidaud, Isabelle; Briec, François et al. (2016) G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block. Proc Natl Acad Sci U S A 113:E932-41|
|Slesinger, Paul A; Wickman, Kevin (2015) Preface. Int Rev Neurobiol 123:xi-xii|
|Ostrovskaya, Olga; Xie, Keqiang; Masuho, Ikuo et al. (2014) RGS7/G?5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling. Elife 3:e02053|
|Luján, Rafael; Marron Fernandez de Velasco, Ezequiel; Aguado, Carolina et al. (2014) New insights into the therapeutic potential of Girk channels. Trends Neurosci 37:20-9|
|Mesirca, Pietro; Alig, Jacqueline; Torrente, Angelo G et al. (2014) Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. Nat Commun 5:4664|
|Wydeven, Nicole; Marron Fernandez de Velasco, Ezequiel; Du, Yu et al. (2014) Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297. Proc Natl Acad Sci U S A 111:10755-60|
|Wydeven, Nicole; Posokhova, Ekaterina; Xia, Zhilian et al. (2014) RGS6, but not RGS4, is the dominant regulator of G protein signaling (RGS) modulator of the parasympathetic regulation of mouse heart rate. J Biol Chem 289:2440-9|
Showing the most recent 10 out of 15 publications