title: Potent inhibition of L-type Ca2+ currents by a Rad variant associated with congestive heart failure.
abstract: Ca(2+) influx via L-type voltage-gated Ca(2+) 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 CaV1.2 and CaV1.3, 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 CaV1.2 or CaV1.3 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.
authors: Department of Medicine-Cardiology Division, University of Colorado Denver-Anschutz Medical Campus, 12700 East 19th Avenue, P15-8006, B-139, Aurora, CO 80045, USA; Departamento de Fisiología y Biofísica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Venustiano Carranza #2405, San Luis Potosí, SLP 78210, México. Electronic address: umeza@uaslp.mx.
authors: U
authors: U
authors: Meza
authors: D
authors: D
authors: Beqollari
authors: C F
authors: CF
authors: Romberg
authors: S
authors: S
authors: Papadopoulos
authors: R A
authors: RA
authors: Bannister
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002460:Cell Line; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); C084355:RRAD protein, human; C490030:Rrad protein, mouse; D018631:ras Proteins
keywords: Ca(V)1.2; Ca(V)1.3; EC; Heart failure; L-type; RGK; RGK protein; Rad; Rad-Rem-Rem2-Gem/Kir protein; RyR2; SR; excitation–contraction; sarcoplasmic reticulum; type 2 ryanodine-sensitive intracellular Ca(2+) release channel