Rem, Rem2, Rad, and Gem/Kir (RGK) represent a distinct GTPase family with largely unknown physiological functions. We report here that both Rem and Rad bind directly to Ca²⁺ channel β-subunits (Ca_Vβ) in vivo. No calcium currents are recorded from human embryonic kidney 293 cells coexpressing the L type Ca²⁺ channel subunits Ca_V1.2, Ca_Vβ_2a, and Rem or Rad, but Ca_V1.2 and Ca_Vβ_2a transfected cells elicit Ca²⁺ channel currents in the absence of these small G proteins. Importantly, Ca_V3 (T type) Ca²⁺ channels, which do not require accessory subunits for ionic current expression, are not inhibited by expression of Rem. Rem is expressed in primary skeletal myoblasts and, when overexpressed in C2C12 myoblasts, wild-type Rem inhibits L type Ca²⁺ channel activity. Deletion analysis demonstrates a critical role for the Rem C terminus in both regulation of functional Ca²⁺ channel expression and β-subunit association. These results suggest that all members of the RGK GTPase family, via direct interaction with auxiliary β-subunits, serve as regulators of L type Ca²⁺ channel activity. Thus, the RGK GTPase family may provide a mechanism for achieving cross talk between Ras-related GTPases and electrical signaling pathways.