Physiological contribution and molecular details of GIRK-dependent signaling in the heart

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Physiological contribution and molecular details of GIRK-dependent signaling in the heart

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2020-07

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Activation of parasympathetic signaling to the heart results in a slowing of heart rate (HR) and an increase in heart rate variability (HRV). Perturbations in parasympathetic signaling to the heart contributes to the pathogenesis of cardiac arrhythmias such as atrial fibrillation. Accordingly, understanding the molecular mechanisms that facilitate the effects of parasympathetic signaling to the heart may provide insight for novel therapeutic interventions for related rhythm disorders. Parasympathetic signaling to the heart is carried largely by the vagus nerve which, when activated, results in activation of muscarinic receptors (M2R) on cardiomyocytes. M2R activation results in the modulation of several ion channels and enzymes, including activation of G protein gated inwardly rectifying potassium (GIRK) channels. The work in this thesis provides a thorough investigation into the physiological relevance of GIRK-dependent signaling in the heart while also probing the details of the underlying signaling architecture. Previous work with parasympathomimetic compounds and global GIRK knockout mice suggested that GIRK channels mediate approximately 50% of the effects of parasympathetic signaling on HR and HRV. Here, we found that mice lacking GIRK channels selectively in atrial and sinoatrial nodal (SAN) tissue displayed absent responses to the HR slowing and HRV increases upon direct vagus nerve stimulation (VNS). Furthermore, GIRK channel ablation in atrial/SAN tissue conferred resistance to VNS-induced arrhythmias. Thus, GIRK channels in the atria represent an attractive therapeutic target for parasympathetic-mediated arrhythmias. Unlike in the atria, the details and relevance of GIRK-dependent signaling in the ventricles are less well known. Electrophysiological recordings in isolated mouse ventricular myocytes revealed a similar GIRK channel subunit composition to those in the atria, however, many attributes (amplitude, sensitivity, kinetics, regulation) were distinct from atrial/SAN counterparts. Furthermore, while GIRK channels mediated the effects of muscarinic stimulation on isolated ventricular myocyte excitability, specific ventricular ablation of GIRK channels in mice showed no impact on the mouse QT interval or ventricular arrhythmia susceptibility. In summary, disruption of ventricular GIRK channel dependent signaling does not appear to predispose the heart to arrhythmias. Work presented here, and in the literature, supports the contention that inhibition of GIRK channel activity has promising therapeutic implications for supraventricular arrhythmias. Accordingly, we characterized a novel GIRK channel inhibitor, VU0468554. VU0468554 afforded dose-dependent block of GIRK channel activation in SAN cells with only minimal antagonism of GIRK channel activity in neurons, which express a different subunit composition. In the isolated mouse heart, VU0468554 exhibited a moderate, yet significant reversal of GIRK-mediated bradycardia elicited by muscarinic activation. Therefore, VU0468554 represents a novel pharmacological tool with therapeutic implications. In addition to M2R activation, GIRK channels are also activated by adenosine 1 receptor (A1R) activation which is exploited clinically for the diagnosis and treatment of certain arrhythmias. We noted that M2R- and A1R-GIRK channel signaling exhibit distinct characteristics and are uniquely regulated by regulator of G protein signaling 6 (RGS6) in mouse SAN cells. These differences appear to arise from a combination of distinct G protein preferences by M2R and A1R and a strong substrate preference by RGS6. Altogether, the GIRK channel signaling network present in the heart represents a critical mediator of cardiac parasympathetic signaling with promising therapeutic implications.

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University of Minnesota Ph.D. dissertation. July 2020. Major: Pharmacology. Advisor: Kevin Wickman. 1 computer file (PDF); vii, 182 pages.

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Anderson, Allison. (2020). Physiological contribution and molecular details of GIRK-dependent signaling in the heart. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/241769.

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