Interactions Between Phospholipase C‐Coupled and N ‐Methyl‐D‐Aspartate Receptors in Cultured Cerebellar Granule Cells: Protein Kinase C Mediated Inhibition of N ‐Methyl‐D‐Aspartate Responses

The N ‐methyl‐D‐aspartate (NMDA) receptor of rat cerebellar granule cells in primary culture is inhibited by phospholipase C‐coupled receptor activation. In the absence of ionotropic agonist, cells modulate their cytoplasmic free Ca 2+ , [Ca 2+ ] c , in response to stimulation of M 3 muscarinic receptors, metabotropic glutamate receptors, and endothelin receptors by the respective agonists carbachol, trans ‐l‐amino‐l,3‐cyclopentanedicarboxylic acid, and endothelin‐1. The response is consistent with the ability of phospholipase C‐coupled receptors to release a pool of intracellular Ca 2+ and induce a subsequent Ca 2+ entry into the cell; both of these responses can be abolished by discharge of internal Ca 2+ stores with low concentrations of ionomycin or thapsigargin. In the case of cells stimulated with NMDA, the [Ca 2+ ] c response to the phospholipase C‐coupled agonists is complex and agonist dependent; however, in the presence of ionomycin each agonist produces a partial inhibition of the NMDA component of the [Ca 2+ ] c signal. This inhibition can be mimicked by the protein kinase C activator 4β‐phorbol 12,13‐dibutyrate. It is concluded that NMDA receptors on cerebellar granule cells are inhibited by phospholipase C‐coupled muscarinic M 3 , glutamatergic, and endothelin receptors via activation of protein kinase C.