CaV2.1 channels are modulated by muscarinic M1 receptors through phosphoinositide hydrolysis in neostriatal neurons.
In adult neostriatal projection neurons, the intracellular Ca(2+) supplied by Ca(V)2.1 (P/Q) Ca(2+) 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 M(1)-class receptors modulates Ca(V)2.1 channels in these neurons in rats. This modulation is reversible, is not membrane delimited, is blocked by the specific M(1)-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 Ca(V)2.1 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)P(2)] blocked all muscarinic modulation of this channel. The results indicate that muscarinic M(1) modulation of Ca(V)2.1 Ca(2+) channels in these neurons involves phosphoinositide hydrolysis.
Perez-Burgos
A
A
Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
Prieto
G A
GA
Galarraga
E
E
Bargas
J
J
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D002478:Cells, Cultured; D004546:Elapid Venoms / Q000494:pharmacology; D006868:Hydrolysis; D042541:Intracellular Space / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D019870:1-Phosphatidylinositol 4-Kinase; D019703:Calcineurin; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D004546:Elapid Venoms; D019269:Phosphatidylinositol 4,5-Diphosphate; D011493:Protein Kinase C; D043643:Receptor, Muscarinic M1; D010738:Type C Phospholipases; C491367:Cacna1a protein, rat; C419876:muscarinic toxin 7