Selective Blockade of P/Q-Type Calcium Channels by the Metabotropic Glutamate Receptor Type 7 Involves a Phospholipase C Pathway in Neurons

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Abstract
Although presynaptic localization of mGluR7 is well established, the mechanism by which the receptor may control Ca2+channels in neurons is still unknown. We show here that cultured cerebellar granule cells express native metabotropic glutamate receptor type 7 (mGluR7) in neuritic processes, whereas transfected mGluR7 was also expressed in cell bodies. This allowed us to study the effect of the transfected receptor on somatic Ca2+ channels. In transfected neurons, mGuR7 selectively inhibited P/Q-type Ca2+ channels. The effect was mimicked by GTPγS and blocked by pertussis toxin (PTX) or a selective antibody raised against the G-protein αo subunit, indicating the involvement of a Go-like protein. The mGuR7 effect did not display the characteristics of a direct interaction between G-protein βγ subunits and the α1A Ca2+ channel subunit, but was abolished by quenching βγ subunits with specific intracellular peptides. Intracellular dialysis of G-protein βγ subunits did not mimic the action of mGluR7, suggesting that both G-protein βγ and αo subunits were required to mediate the effect. Inhibition of phospholipase C (PLC) blocked the inhibitory action of mGluR7, suggesting that a coincident activation of PLC by the G-protein βγ with αo subunits was required. The Ca2+ chelator BAPTA, as well as inhibition of either the inositol trisphosphate (IP3) 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 synaptic transmission by the present mechanisms is discussed.