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RhoA GTPase regulates L-type Ca²⁺ currents in cardiac myocytes

¹Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey; and ²Department of Medicine and Department of Molecular and Cellular Biology, Section of Cardiovascular Sciences, Center for Cardiovascular Development, DeBakey Heart Center, Baylor College of Medicine and Methodist Hospital, Houston, Texas

Submitted 23 March 2004 ; accepted in final form 1 October 2004

Regulation of ionic channels plays a pivotal role in controlling cardiac function. Here we show that the Rho family of small G proteins regulates L-type Ca²⁺ currents in ventricular cardiomyocytes. Ventricular myocytes isolated from transgenic (TG) mice that overexpress the specific GDP dissociation inhibitor Rho GDI- exhibited significantly decreased basal L-type Ca²⁺ current density (40%) compared with myocytes from nontransgenic (NTG) mice. The Ca²⁺ channel agonist BAY K 8644 and the -adrenergic agonist isoproterenol increased Ca²⁺ currents in both NTG and TG myocytes to a similar maximal level, and no changes in mRNA or protein levels were observed in the Ca²⁺ channel ₁-subunits. These results suggest that the channel activity but not the expression level was altered in TG myocytes. In addition, the densities of inward rectifier and transient outward K⁺ currents were unchanged in TG myocytes. The amplitudes and rates of basal twitches and Ca²⁺ transients were also similar between the two groups. When the protein was delivered directly into adult ventricular myocytes via TAT-mediated protein transduction, Rho GDI- significantly decreased Ca²⁺ current density, which supports the idea that the defective Ca²⁺ channel activity in TG myocytes was a primary effect of the transgene. In addition, expression of a dominant-negative RhoA but not a dominant-negative Rac-1 or Cdc42 also significantly decreased Ca²⁺ current density, which indicates that inhibition of Ca²⁺ channel activity by overexpression of Rho GDI- is mediated by inhibition of RhoA. This study points to the L-type Ca²⁺ channel activity as a novel downstream target of the RhoA signaling pathway.

GDP dissociation inhibitor; TAT-mediated protein transduction; K⁺ channel; ventricular; cardiomyocyte

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