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

Voltage-dependent calcium (Ca 2+ ) channels are involved in many specialized cellular functions 1 , 2 , 3 , and are controlled by intracellular signals such as 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 Ca 2+ channels is unclear. We report here that the GTP-bound form of kir/Gem, identified originally as a Ras-related small G-protein that binds CaM 9 , 10 , 11 , inhibits high-voltage-activated Ca 2+ channel activities by interacting directly with the β-subunit. The reduced channel activities are due to a decrease in α 1 -subunit expression at the plasma membrane. The binding of Ca 2+ /CaM to kir/Gem is required for this inhibitory effect by promoting the cytoplasmic localization of kir/Gem. Inhibition of L-type Ca 2+ channels by kir/Gem prevents Ca 2+ -triggered exocytosis in hormone-secreting cells. We propose that the small G-protein kir/Gem, interacting with β-subunits, regulates Ca 2+ channel expression at the cell surface.