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Meza, U., Beqollari, D., Romberg, C. F., Papadopoulos, S. and Bannister, R. A. (2013). Potent inhibition of L-type Ca2+ currents by a Rad variant associated with congestive heart failure. Biochem. Biophys. Res. Commun., 439 (2). S. 270 - 275. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1090-2104

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Abstract

Ca2+ influx via L-type voltage-gated Ca2+ channels supports the plateau phase of ventricular action potentials and is the trigger for excitation-contraction (EC) coupling in the myocardium. Rad, a member of the RGK (Rem, Rem2, Rad, Gem/Kir) family of monomeric G proteins, regulates ventricular action potential duration and EC coupling gain through its ability to inhibit cardiac L-type channel activity. In this study, we have investigated the potential dysfunction of a naturally occurring Rad variant (Q66P) that has been associated with congestive heart failure in humans. Specifically, we have tested whether Rad Q66P limits, or even eliminates, the inhibitory actions of Rad on Ca(V)1.2 and Ca(V)1.3, the two L-type channel isoforms known to be expressed in the heart. We have found that mouse Rad Q65P (the murine equivalent of human Rad Q66P) inhibits L-type currents conducted by Ca(V)1.2 or Ca(V)1.3 channels as potently as wild-type Rad (>95% inhibition of both channels). In addition, Rad Q65P attenuates the gating movement of both channels as effectively as wild-type Rad, indicating that the Q65P substitution does not differentially impair any of the three described modes of L-type channel inhibition by RGK proteins. Thus, we conclude that if Rad Q66P contributes to cardiomyopathy, it does so via a mechanism that is not related to its ability to inhibit L-type channel-dependent processes per se. However, our results do not rule out the possibility that decreased expression, mistargeting or altered regulation of Rad Q66P may reduce the RGK protein's efficacy in vivo. (C) 2013 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Meza, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Beqollari, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Romberg, C. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Papadopoulos, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bannister, R. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-475786
DOI:	10.1016/j.bbrc.2013.08.044
Journal or Publication Title:	Biochem. Biophys. Res. Commun.
Volume:	439
Number:	2
Page Range:	S. 270 - 275
Date:	2013
Publisher:	ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication:	SAN DIEGO
ISSN:	1090-2104
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DEPENDENT CALCIUM-CHANNELS; RGK FAMILY; CA(V)1.2 CHANNELS; REM; EXPRESSION; GTPASE; OVEREXPRESSION; MODULATION; MECHANISMS; CLONING Multiple languages Biochemistry & Molecular Biology; Biophysics Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47578