NEURAL CONTROL OF ION CHANNELS AND AUTONOMIC RESPONSE

The overall goal is to define the nature and time course of developmental changes in myocardial ion channel function and autonomic responsiveness, and the mechanism(s) through which these changes are achieved. This goal derives from our hypothesis (based on prior work under this PPG) that are sympathetic innervation exerts a trophic influence on cardiac phenotype maturation, thereby inducing significant changes in myocardial electrophysiology and pharmacology. Recent studies under Project D have identified important developmental changes in ionic currents contributing to sinus node impulse initiation (I/Na), ventricular pacemaking (I/f), the plateau (I/CaL) and phase 3 repolarization (I/K1, I/to). Yet the factors, neuronal and otherwise, that are responsible for regulation of these currents are unknown. Project D will determine the nature of the developmental changes in these currents and extent to which, and mechanism by which, innervation contributes to them. To attain this end we use an in vitro approach that permits the direct control of the micro-environment of myocardial cell in culture, and includes the ability to functionally innervate myocytes in culture with sympathetic neurons. Our first aim, which follows from our recent discovery of a neuronal type I-like Na current in neonatal sinus node myocytes, is to determine the implications of this current for autonomic control of normal sinus rhythm in the young heart, and investigate the factor(s) responsible for the age-dependent loss of this current. Our second aim, which arises from recent data on the developmental and innervation dependent shift in the activation voltage pacemaker current I/f, includes studying the time course of the developmental shift in I/f, the mechanism by which innervation modulates the current (i.e. the neural factor) and the basis of the change in current-in particular the role of protein kinase C and phosphorylation. Our third aim, which derives from data indicating that innervation is likely to regulate I/CaL, via neurally released NPY, is to determine the mechanism by which innervation and NPY modulate I/CaL, as well as to further elucidate the contribution of sympathetic innervation to the developmental maturation of the repolarizing currents I/k1 and I/to. By studying the changes in heart rate and repolarization that occur developmentally and their sympathetic modulation, we will not only improve our understanding of the mechanism that regulate normal electrophysiological function, but will provide a framework for understand how arrhythmogenic interventions-studied in other Projects-impact on normal function.