Three different classes of alpha 1 Ca2+ channel (alpha 1A, alpha 1B, alpha 1C) were expressed in Xenopus oocytes to determine whether G protein-mediated inhibition is an inherent property of the alpha 1 subunit itself, and if so, whether co-expression of auxiliary subunits modulates the inhibition seen. From our data it is apparent that either alpha 1A or alpha 1B Ca2+ channels expressed alone are sufficient for voltage-dependent G protein inhibition. alpha 1C Ca2+ channels expressed alone do not exhibit the G protein inhibition seen in alpha 1A and alpha 1B channels. Additionally, co-expression of the beta 3 subunit abolishes the ability of G proteins to inhibit currents through alpha 1A and alpha 1B Ca2+ channels. Differential sensitivity of alpha 1 as well as modulation of properties by beta 3 provide a potential mechanism for the regulation of G protein-mediated inhibition in neurons.