Auxiliary Cavβ subunits of the high voltage L‐type Ca2+ channels modulate the low voltage activated cardiac Cav3.2 T‐type Ca2+ channel currents

Abstract

Ca2+ signaling and contraction are initiated by the activation of high voltage L‐type Ca2+ channels (LTCC) in cardiomyocytes. However, pathological hypertrophic Ca2+ signaling results from the re‐expression of low voltage T‐type Ca2+ channel (TTCC) current. But the precise regulation of the cardiac TTCC isoforms, Cav3.1 and Cav3.2, in cardiac hypertrophy is unclear. While the Cavβ subunits (isoforms β1, β2, β3 and β4) of the LTCC are required for membrane trafficking and functional regulation of the Cav1.2 subunit of LTCC, auxiliary subunits for the TTCCs have not been identified. We investigated if the β subunits of the LTCC regulate the function of low voltage activated cardiac TTCCs. Co‐immunoprecipitation performed in transiently expressing HEK293 cells or hypertrophic mouse cardiomyocytes demonstrated that the β1, β2 and β3 but not the β4 subunits co‐IP with Cav3.2 channel protein. Whole cell patch clamp analysis in transiently expressed HEK293 cells demonstrate that β1 and β2 subunits caused a significant increase in ICav3.2 density but not ICav3.1. In contrast the β3 and β4 did not alter the ICav3.2 or ICav3.1 density. In addition, the co‐expression of β1 caused a rightward shift in the V1/2 of ICav3.2 activation. We also found that the expression of the β1 and β2 subunits was increased in ventricular myocytes in mouse model of pressure overload induced cardiac hypertrophy. We conclude that an increased expression of the β1 and β2 subunits may regulate the ICav3.2 and contribute to the altered Ca2+ signaling in pathological cardiac hypertrophy. Research support NHLBI R01HL105713 to RCB.