Rationale: The L-type calcium channels (LTCC) are critical for maintaining Ca2+-homeostasis. In heterologous expression studies, the RGK-class of Ras-related G-proteins regulates LTCC function; however, the physiological relevance of RGKLTCC interactions is untested. Objective: In this report we test the hypothesis that the RGK protein, Rem, modulates native Ca2+ current (ICa,L) via LTCC in murine cardiomyocytes. Methods and Results: Rem knockout mice (Rem-/-) were engineered, and ICa,L and Ca2+-handling properties were assessed. Rem-/- ventricular cardiomyocytes displayed increased ICa,L density. ICa,L activation was shifted positive on the voltage axis, and β-adrenergic stimulation normalized this shift compared with wild-type ICa,L. Current kinetics, steady-state inactivation and facilitation was unaffected by Rem-/-. Cell shortening was not significantly different. Increased ICa,L density in the absence of frank phenotypic differences motivated us to explore putative compensatory mechanisms. Despite the larger ICa,L density, Rem-/- cardiomyocyte Ca2+ twitch transient amplitude was significantly less than that compared with wild type. Computer simulations and immunoblot analysis suggests that relative dephosphorylation of Rem-/- LTCC can account for the paradoxical decrease of Ca2+ transients. Conclusions: This is the first demonstration that loss of an RGK protein influences ICa,L in vivo in cardiac myocytes.
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