Molecular mechanisms of regulation of fast-inactivating voltage-dependent transient outward K+ current in mouse heart by cell volume changes.
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.
Wang
Guan-Lei
GL
Center of Biomedical Research Excellence, Department of Pharmacology, University of Nevada School of Medicine, Reno, 89557-0270, USA.
Wang
Ge-Xin
GX
Yamamoto
Shintaro
S
Ye
Linda
L
Baxter
Heather
H
Hume
Joseph R
JR
Duan
Dayue
D
D000200:Action Potentials; D000818:Animals; D048429:Cell Size; D004789:Enzyme Activation; D006352:Heart Ventricles / Q000378:metabolism; D007038:Hypotonic Solutions; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009997:Osmotic Pressure; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D007038:Hypotonic Solutions; D051672:Shal Potassium Channels; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases