Voltage-dependent calcium (Ca²⁺) channels are involved in many specialized cellular functions^,,, and are controlled by intracellular signals such as heterotrimeric G-proteins, protein kinases^, and calmodulin (CaM)^,. 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, identified originally as a Ras-related small G-protein that binds CaM^,,, inhibits high-voltage-activated Ca²⁺ channel activities by interacting directly with the β-subunit. The reduced channel activities are due to a decrease in α₁-subunit expression at the plasma membrane. The binding of Ca²⁺/CaM to kir/Gem is required for this inhibitory effect by promoting the cytoplasmic localization of kir/Gem. Inhibition of L-type Ca²⁺ channels by kir/Gem prevents Ca²⁺-triggered exocytosis in hormone-secreting cells. We propose that the small G-protein kir/Gem, interacting with β-subunits, regulates Ca²⁺ channel expression at the cell surface.