ACTIVATION OF A METABOTROPIC GLUTAMATE-RECEPTOR AND PROTEIN-KINASE-C REDUCE THE EXTENT OF INACTIVATION OF THE K+ CHANNEL KV1.1 KV-BETA-1.1 VIA DEPHOSPHORYLATION OF KV1.1/

Various brain K+ channels, which may normally exist as complexes of al pha (pore-farming) and beta (auxiliary) subunits, were subjected to re gulation by metabotropic glutamate receptors, Kv1.1/Kv beta 1.1 is a v oltage-dependent K+ channel composed of alpha and beta proteins that a re widely expressed in the brain, Expression of this channel in Xenopu s oocytes resulted in a current that had fast inactivating and noninac tivating components, Previously we showed that basal and protein kinas e A-induced phosphorylation of the alpha subunit at Ser-446 decreases the fraction of the noninactivating component. In this study we invest igated the effect of protein kinase C (PKC) on the channel. We showed that a PHC-activating phorbol ester (phorbol 12-myristate 13-acetate ( PMA)) increased the noninactivating fraction via activation of a PKC s ubtype that was inhibited by staurosporine and bisindolylmaleimide but not by calphostin C. However, it was not a PKC-induced phosphorylatio n but rather a dephosphorylation that mediated the effect. PMA reduced the basal phosphorylation of Ser-446 significantly in plasma membrane channels and failed to affect the inactivation of channels having an cu subunit that was mutated at Ser-446, Also, the activation of coexpr essed mGluR1a known to activate phospholipase C mimicked the effect of PMA on the inactivation via induction of dephosphorylation at Ser-446 , Thus, this study identified a potential neuronal pathway initiated b y activation of metabotropic glutamate receptor fa coupled to a signal ing cascade that possibly utilized PKC to induce dephosphorylation and thereby to decrease the extent of inactivation of a KC channel.