Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem

Voltage-dependent calcium (Ca2+) channels are involved in many specialized cellular functions(1-3), and are controlled by intracellular signals such a s heterotrimeric G-proteins(4), protein kinases(5,6) and calmodulin (CaM)(7 ,8). However, the direct role of small G-proteins in the regulation of Ca2 channels is unclear. We report here that the GTP-bound form of kir/Gem, id entified originally as a Ras-related small G-protein that binds CaM9-11, in hibits high-voltage-activated Ca2+ channel activities by interacting direct ly with the beta -subunit. The reduced channel activities are due to a decr ease in alpha (1)-subunit expression at the plasma membrane. The binding of Ca2+/CaM to kir/Gem is required for this inhibitory effect by promoting th e cytoplasmic localization of kir/Gem. Inhibition of L-type Ca2+ channels b y kir/Gem prevents Ca2+ triggered exocytosis in hormone-secreting cells. We propose that the small G-protein kir/Gem, interacting with beta -subunits, regulates Ca2+ channel expression at the cell surface.