Molecular Pathways of Heart K Channel Regulation

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): The long term goal is to unravel cellular and molecular mechanisms involved in cardiac-electrical and molecular-remodeling during functional hypertrophy in pregnancy, and recovery in postpartum; in particular, those related to K+ channel expression/function. I to K+ shapes the cardiac action potential duration in both rodents and humans. In failing hypertrophic hearts, I to-f molecular components, in particular Kv4.3 and Kv4.2 channels are downregulated increasing action potential duration and arrhythmogenesis. During pregnancy, there is an increased risk of arrhythmias, the heart develops functional hypertrophy, and hormone levels dramatically change; however, no studies are available on changes in K+ expression/function induced by sex hormones, that may explain the cardiac risks during pregnancy or their reversibility after delivery. Thus, the main hypothesis is that, during pregnancy and postpartum, sex hormones may regulate I to current components (e.g. Kvl.4, Kv4.2, Kv4.3, KChlP2, MiRP1, frequenin) in a genomic or non-genomic fashion. Preliminary Studies show that: (a) cardiac Kv4.3, Kvl.4 and KCh/P2, but not Kv4.2 channel transcripts, and Kv4.3 protein were reduced in late pregnancy; (b) as in pregnancy, 17-beta-estradiol (E2) treatment reduced cardiac Kv4.3 and Kvl.4 mRNA; (c) E2 reduced Kv4.3 protein expression in cultured adult myocytes; (d) E2 had dual effects on I to currents, at 100 nM (similar to late human pregnancy), it shortened the action potential and increased I to amplitude; whereas, an opposite effect was produced by 10 fM E2; (e) c-Src tyrosine kinase, which is activated by E2 and from the onset of hypertrophy, reduced expression of Kv4.3; and (f) tyrosine kinase activation produced action potential prolongation and I to current reduction. We will mainly use mice and multiple experimental approaches. The Specific Aims are to: (1) Investigate, during pregnancy and early postpartum, the remodeling of action potentials, and of I to fast (I to-f) and I to slow (I to-s) currents, and underlying molecular components. (2) Investigate the action of E2 on I to-f/I to-s currents and their molecular components, and if E2 stimulates Kv4.3 gene transcription through the c-Src/MAPK (ERK) axis. (3) Characterize and define the mechanism(s) of non-genomic regulation of I to-f and Kv4.3 channels by E2. (4) Investigate short- and long-term actions of c-Src-dependent tyrosine phosphorylation on I to currents and Kv4 isoforms. (5) Determine the motifs in Kv4.3 involved in its regulation by c-Src. These studies should provide new information on the cellular and molecular mechanisms leading to the remodeling of cardiac K+ channels in the early stages of hypertrophy, and help in the design of new strategies for preventive Medicine.