Group I mGluRs heterologously expressed in sympathetic neurons inhibited calcium (I(Ca)) and M-type potassium (I(M)) currents. Treatment with pertussis toxin (PTX) revealed a voltage-dependent (VD), PTX-sensitive component of I(Ca) inhibition and a voltage-independent (VI), PTX-insensitive component. Coexpression of RGS2 occluded mGluR1a inhibition of I(M) and made I(Ca) inhibition VD in PTX-treated cells, presumably by blocking the effects of G alpha(q/11)-GTP. These data indicate that mGluR1a can couple to G(i/o) as well as G(q/11). In addition, VI I(Ca) inhibition proceeds through a G alpha(q/11)-GTP-mediated pathway, which can be occluded by expressing RGS2, leaving the VD, G betagamma-mediated inhibition active. These data may reveal a functional role for the upregulation of RGS2 expression in in vivo systems.