GABA_B receptor activation elicits both voltage-dependent and voltage-independent inhibition of Ca_V2 current. (A) After GABA_B receptor activation, Ca_V2 family members exhibit distinct modulation by voltage-dependent (VD) and/or voltage-independent (VI) current inhibition. (B) Example current traces illustrate the two forms of modulation. (Left traces) VD inhibition exhibits slowed kinetics (red traces) compared with control (black) currents that is relieved with positive prepulses (PP). (Right traces) VI inhibition (VI) remains following a PP. (C) Schematic of the proposed mechanism for Ca_V2 inhibition by the two pathways. GABA_B1 and GABA_B2 subunits form the GABA_B receptor. GABA or baclofen binds to the B1 subunit, activating the receptor. cVc1.1 (V) binds at an undefined site within the interface of the two subunits. Activated Gβγ binds to multiple sites (red squares), whereas Gα stimulates c-src kinase to phosphorylate tyrosine residues (blue circles) in the C-terminal tail of certain Ca_V2 family members. Black squares, Ca_Vβ high affinity–binding sites.