Selective blockade of P/Q-type calcium channels by the metabotropic glutamate receptor type 7 involves a phospholipase C pathway in neurons

Although presynaptic localization of mGluR7 is well established, the mechan ism by which the receptor may control Ca2+ channels in neurons is still unk nown. We show here that cultured cerebellar granule cells express native me tabotropic glutamate receptor type 7 (mGluR7) in neuritic processes, wherea s transfected mGluR7 was also expressed in cell bodies. This allowed us to study the effect of the transfected receptor on somatic Ca2+ channels. In t ransfected neurons, mGuR7 selectively inhibited P/Q-type Ca2+ channels. The effect was mimicked by GTP gammaS and blocked by pertussis toxin (PTX) or a selective antibody raised against the G-protein alphao subunit, indicatin g the involvement of a G(o)-like protein. The mGuR7 effect did not display the characteristics of a direct interaction between G-protein beta gamma su bunits and the alpha 1A Ca2+ channel subunit, but was abolished by quenchin g beta gamma subunits with specific intracellular peptides. Intracellular d ialysis of G-protein beta gamma subunits did not mimic the action of mGluR7 , suggesting that both G-protein beta gamma and alphao subunits were requir ed to mediate the effect. Inhibition of phospholipase C (PLC) blocked the i nhibitory action of mGluR7, suggesting that a coincident activation of PLC by the G-protein beta gamma with alphao subunits was required. The Ca2+ che lator BAPTA, as well as inhibition of either the inositol trisphosphate (IP 3) receptor or protein kinase C (PKC) abolished the mGluR7 effect. Moreover , activation of native mGluR7 induced a PTX-dependent IP3 formation. These results indicated that IP3 mediated intracellular Ca2+ release was required for PKC-dependent inhibition of the Ca2+ channels. Possible control of syn aptic transmission by the present mechanisms is discussed.