Date of Completion

4-28-2017

Embargo Period

4-27-2019

Major Advisor

Dr. Bruce Liang

Co-Major Advisor

Dr. Leslie Loew

Associate Advisor

Dr. Kimberly Dodge-Kafka

Associate Advisor

Dr. Lixia Yue

Associate Advisor

Dr. Ion Moraru

Associate Advisor

Dr. Yi Wu

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Purinergic receptors respond to extracellular nucleotides and their metabolites. They act as important signaling transduction molecules in a variety of biological processes and are important in a number of pathophysiologic conditions that impact human health. A subset of these receptors acts as non-selective cation channels, designated as P2X receptors, which can induce electrical activities in the cellular membrane and thus impact cellular function. A number of longitudinal studies following surgically or genetically induced heart failure animals have demonstrated potential improvement of cardiac function with P2X4 receptor overexpression. We explore here how P2X signaling affects cardiomyocyte excitability and leads to changes in contraction in both computational and experimental models. We confirm computational predictions of P2X induced membrane depolarization and subsequent changes in a number of cardiomyocyte currents using whole cell patch clamp techniques. Direct sodium cxxxentry via P2X channels leading to intracellular ion concentration changes were detected with an increase in Na+-K+ ATPase peak current and enhancement of the calcium entry mode of the Na+-Ca2+ exchanger. The latter we show may play a role in the enhancement of contractile response by extracellular ATP. With the aid of computational prediction and interpretation, our findings highlight the value of dynamic considerations of channel currents and offer explanations for prior inconsistencies in the purinergic field. Moreover, we establish an interaction between the P2X4 receptor and nitric oxide production that may underlie its cardioprotective effects after myocardial injury. This improved understanding of P2X action on the heart helps to improve our evaluation of its targeting in clinical applications.

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