Calcium channel gamma6 subunits are unique modulators of low voltage-activated (Cav3.1) calcium current.

The calcium channel gamma (gamma) subunit family consists of eight members whose functions include modulation of high voltage-activated (HVA) calcium currents in skeletal muscle and neurons, and regulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propanoic acid (AMPA) receptor targeting. Cardiac myocytes express at least three gamma subunits, gamma(4), gamma(6) and gamma(7), whose function(s) in the heart are unknown. Here we compare the effects of the previously uncharacterized gamma(6) subunit with that of gamma(4) and gamma(7) on a low voltage-activated calcium channel (Cav3.1) that is expressed in cardiac myocytes. Co-expression of both the long and short gamma(6) subunit isoforms, gamma(6L) and gamma(6S), with Cav3.1 in HEK-293 cells significantly decreases current density by 49% and 69%, respectively. Two other gamma subunits expressed in cardiac myocytes, gamma(4) and gamma(7), have no significant effect on Cav3.1 current. Neither gamma(6L), gamma(6S), gamma(4) nor gamma(7) significantly affect the voltage dependency of activation or inactivation or the kinetics of Cav3.1 current. Transient expression of gamma(6L) in an immortalized atrial cell line (HL-1) significantly reduces the endogenous low voltage-activated current in these cells by 63%. Green fluorescent protein tagged gamma(6L) is localized primarily in HEK-293 cell surface membranes where it is evenly distributed. Expression of gamma(6L) does not affect the level of Cav3.1 mRNA or the amount of total Cav3.1 protein in transfected HEK-293 cells. These results demonstrate that the gamma(6) subunit has a unique ability to inhibit Cav3.1 dependent calcium current that is not shared with the gamma(4) and gamma(7) isoforms and is thus a potential regulator of cardiac low voltage-activated calcium current.