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The Journal of Neuroscience, November 1, 2000, 20(21):7896-7904

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

Julie Perroy¹, Laurent Prezeau¹, Michel De Waard², Ryuichi Shigemoto³, Joel Bockaert¹, and Laurent Fagni¹

¹ Centre National de la Recherche Scientifique, Unité Propre de Recherche 9023, Centre CNRS-INSERM de Pharmacologie et d'Endocrinologie, 34000 Montpellier, France, ² Institut National de la Santé et de la Recherche Médicale, U-464, Faculté de Médecine Nord, 13916 Marseilles, France, and ³ Laboratory of Cerebral Structure, National Institute for Physiological Sciences, CREST Japan Science and Technology Corporation, Myodaiji, Okazaki 444-8585, Japan

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 GTPS and blocked by pertussis toxin (PTX) or a selective antibody raised against the G-protein o subunit, indicating the involvement of a G_o-like protein. The mGuR7 effect did not display the characteristics of a direct interaction between G-protein subunits and the 1A Ca²⁺ channel subunit, but was abolished by quenching subunits with specific intracellular peptides. Intracellular dialysis of G-protein subunits did not mimic the action of mGluR7, suggesting that both G-protein and o 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 with o 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.

Key words: mGluR7; Ca²⁺ channels; G-protein; PLC; cerebellar granule cells; transfection

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20217896-09$05.00/0

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