Direct Interaction and Functional Coupling between Metabotropic Glutamate Receptor Subtype 1 and Voltage-sensitive Ca_v2.1 Ca²⁺ Channel

Intracellular Ca²⁺ concentrations ([Ca²⁺] _i) are regulated in a spatiotemporal manner via both entry of extracellular Ca²⁺ and mobilization of Ca²⁺ from intracellular stores. Metabotropic glutamate receptor subtype 1 (mGluR1) is a G protein-coupled receptor that stimulates the inositol 1,4,5-trisphosphate-Ca²⁺ signaling cascade, whereas Ca_v2. 1 is a pore-forming channel protein of P/Q-type voltage-sensitive Ca ²⁺ channels. In this investigation, we showed that mGluR1 and Ca _v2.1 are colocalized at dendrites of cerebellar Purkinje neurons and form the heteromeric assembly in both the brain and heterologously expressing COS-7 cells. This assembly occurs through the direct interaction between their carboxyl-terminal intracellular domains. Calcium imaging and whole-cell recording showed that mGluR1 inhibits Ca_v2.1-mediated [Ca ²⁺]_i increases and Ba²⁺ currents in HEK 293 cells expressing Ca_v2.1 with auxiliary α2/δ and β1 subunits, respectively. This inhibition occurred in a ligand-independent manner and was enhanced by pre-activation of mGluR1 in a ligand-dependent manner. In contrast, simultaneous stimulation of mGluR1 and Ca_v2.1 induced large [Ca²⁺]_i increases. Furthermore, the temporally regulated inhibition and stimulation of [Ca²⁺]_i increases by mGluR1 and Ca_v2.1 were observed at dendrites but not soma of cultured Purkinje neurons. These data suggest that the assembly of mGluR1 and Ca_v2.1 provides the mechanism that ensures spatiotemporal regulation of [Ca²⁺]_i in glutamatergic neurotransmission.