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Molecular mechanisms of regulation of fast‐inactivating voltage‐dependent transient outward K + current in mouse heart by cell volume changes
Author(s) -
Wang GuanLei,
Wang GeXin,
Yamamoto Shintaro,
Ye Linda,
Baxter Heather,
Hume Joseph R.,
Duan Dayue
Publication year - 2005
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2005.091264
Subject(s) - repolarization , myocyte , okadaic acid , dephosphorylation , medicine , protein kinase c , phosphatase , endocrinology , activator (genetics) , chemistry , cardiac action potential , gating , microbiology and biotechnology , biology , phosphorylation , biophysics , electrophysiology , receptor
The K v 4.2/4.3 channels are the primary subunits that contribute to the fast‐inactivating, voltage‐dependent transient outward K + current ( I to,fast ) in the heart. I to,fast is the critical determinant of the early repolarization of the cardiac action potential and plays an important role in the adaptive remodelling of cardiac myocytes, which usually causes cell volume changes, during myocardial ischaemia, hypertrophy and heart failure. It is not known, however, whether I to,fast is regulated by cell volume changes. In this study we investigated the molecular mechanism for cell volume regulation of I to,fast in native mouse left ventricular myocytes. Hyposmotic cell swelling caused a marked increase in densities of the peak I to,fast and a significant shortening in phase 1 repolarization of the action potential duration. The voltage‐dependent gating properties of I to,fast were, however, not altered by changes in cell volume. In the presence of either protein kinase C (PKC) activator (12,13‐dibutyrate) or phosphatase inhibitors (calyculin A and okadaic acid), hyposmotic cell swelling failed to further up‐regulate I to,fast . When expressed in NIH/3T3 cells, both K v 4.2 and K v 4.3 channels were also strongly regulated by cell volume in the same voltage‐independent but PKC‐ and phosphatase‐dependent manner as seen in I to,fast in the native cardiac myocytes. We conclude that K v 4.2/4.3 channels in the heart are regulated by cell volume through a phosphorylation/dephosphorylation pathway mediated by PKC and serine/threonine phosphatase(s). These findings suggest a novel role of K v 4.2/4.3 channels in the adaptive electrical and structural remodelling of cardiac myocytes in response to myocardial hypertrophy, ischaemia and reperfusion.