CaV2.1 channels are modulated by muscarinic M1 receptors through phosphoinositide hydrolysis in neostriatal neurons

In adult neostriatal projection neurons, the intracellular Ca2+ supplied by CaV2.1 (P/Q) Ca2+ channels is in charge of both the generation of the afterhyperpolarizing potential (AHP) and the release of GABA from their synaptic terminals, thus being a major target for firing pattern and transmitter release modulations. We have shown that activation of muscarinic M1-class receptors modulates CaV2.1 channels in these neurons in rats. This modulation is reversible, is not membrane delimited, is blocked by the specific M1-class muscarinic antagonist muscarine toxin 7 (MT-7), and is neither mediated by protein kinase C (PKC) nor by protein phosphatase 2B (PP-2B). Hence, the signaling mechanism of muscarinic CaV2.1 channel modulation has remained elusive. The present paper shows that inactivation of phospholipase C (PLC) abolishes this modulation while inhibition of phosphoinositide kinases, PI-3K and PI-4K, prevents its reversibility, suggesting that the reconstitution of muscarinic modulation depends on phosphoinositide rephosphorylation. In support of this hypothesis, the supply of intracellular phosphatidylinositol (4,5) bisphosphate [PI(4,5)P2] blocked all muscarinic modulation of this channel. The results indicate that muscarinic M1 modulation of CaV2.1 Ca2+ channels in these neurons involves phosphoinositide hydrolysis.