Abstract 19865: Rem-GTPase Regulates Cardiac Myocyte L-type Calcium Current
The L-type calcium channels (LTCC) are critical for maintaining Ca2+-homeostasis. In turn, Ca2+-homeostasis is critical for cardiac myocyte growth. In heterologous expression studies, the RGK-class of small G-proteins regulates LTCC function; however, the physiological relevance of RGK — LTCC interactions is untested. In this report we test the hypothesis that the RGK protein, Rem, modulates native Ca2+ current (ICa,L) in murine cardiac myocytes. Rem knockout mice (Rem−/−) were engineered, and ICa,L and Ca2+-handling properties were evaluated. In addition, echocardiography and electrocardiograms were used to evaluate cardiac morphology and function. Rem−/− ventricular cardiomyocytes displayed increased ICa,L density. Unexpectedly, cell capacitance was significantly smaller for Rem−/− compared to wild-type cardiomyocytes. ICa,L activation was shifted negative on the voltage axis, and β-adrenergic stimulation normalized this shift compared to wild-type ICa,L. Current kinetics, steady-state inactivation, and facilitation was unaffected by Rem−/−. 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−/− cardiac myocyte Ca2+ twitch transient amplitude was significantly less than that compared to wild-type. Cell shortening was not significantly different. Ambulatory ECG recordings showed an increased basal heart rate normalized by propanolol treatment. Cardiomyocyte size was significantly smaller in Rem-/- compared to wild-type based on capacitance, dispersed cell area, and histological evaluation of cell sections. At the organ level, echocardiography showed borderline smaller hearts compared to wild-type. In summary, as expected from heterologous expression studies of LTCC — RGK protein interactions, Rem−/− mice showed a larger ICa,L density. Surprisingly, the major difference in ICa,L density is attributable to smaller-sized cells without attendant decrease of Ca-channel current per se. We conclude that Rem regulates ICa,L and cardiomyocyte homeostasis via ICa,L.
- © 2010 by American Heart Association, Inc.