Abnormalities of ventricular repolarization have been identified in a number of cardiac disease states and may predispose to malignant or fatal ventricular arrhythmias. The transient outward potassium current, I- to, is an important determinant of ventricular repolarization. The potassium channel isoform responsible for I-to varies between species. Kv1.4, Kv1.5, Kv4.2, and Kv4.3 have been identified as contributors to ventricular repolarization in various species, with Kv1.4, Kv4.2, and Kv4.3 representing the most likely contributors to I-to in canine cardiac myocytes. Decreased I-to density has been found in several pathologic states including myocardial hypertrophy, terminal heart failure, and acute Trypanosoma cruzi infection, and prolonged ventricular repolarization may increase the morbidity and mortality of these conditions. Moise and collaborators have previously reported a line of German Shepherd dogs with inherited ventricular arrhythmias and sudden death. Affected dogs have a decreased sympathetic innervation of the left ventricle and decreased left ventricular I-to density. Norepinephrine application rescues I-to in myocytes isolated from affected regions in these dogs, suggesting that the decreased I-to may result from a loss of the trophic influence of the sympathetic nervous system during development. Nerve growth factor and enkephalins have been shown to promote growth and survival of central and peripheral neurons. Using whole cell patch clamp recording ribonuclease protection assays, and Western blot techniques, we will address the following questions: (1) Is decreased NGF and ppENK expression responsible for the abnormal peripheral sympathetic innervation in the hearts of affected dogs? (2) Which potassium channels (Kv1.4, Kv1.5, Kv4.2, and Kv4.3) are responsible for I-to in affected dogs? Is the decreased expression of one or a combination of these channel isoforms responsible for deceased I-to in affected dogs? Is the increased expression of one or a combination of these isoforms responsible for NE mediated restoration of I-to in affected dogs?, and (3) Is the restoration of I-to by NE in the hearts of affected dogs mediated by alpha or beta adrenergic receptors and their associated second messenger cascades? The scientific training obtained while performing this research in a vital and supportive intellectual environment will provide valuable theoretical and technical experience for the applicant to expand upon his clinical and basic scientific experience to achieve his goal of a link between the basic scientific study of membrane bound ion channels/receptors and clinical cardiology.
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