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¹ Center of Biomedical Research Excellence, Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557-0270, USA

The K_v4.2/4.3 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_v4.2 and K_v4.3 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_v4.2/4.3 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_v4.2/4.3 channels in the adaptive electrical and structural remodelling of cardiac myocytes in response to myocardial hypertrophy, ischaemia and reperfusion.

(Received 24 May 2005; accepted after revision 28 July 2005; first published online 4 August 2005)
Corresponding author D. Duan: Center of Biomedical Research Excellence, Department of Pharmacology, University of Nevada School of Medicine, Manville Medical Building Room no. 9/MS 318, Reno, NV 89557-0270, USA. Email: dduan{at}med.unr.edu

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