Activation of a metabotropic glutamate receptor and protein kinase C reduce the extent of inactivation of the K+ channel Kv1.1/Kvβ1.1 via dephosphorylation of Kv1.1

Various brain K+ channels, which may normally exist as complexes of alpha (pore-farming) and beta (auxiliary) subunits, were subjected to regulation by metabotropic glutamate receptors, Kv1.1/Kv beta 1.1 is a voltage-dependent K+ channel composed of alpha and beta proteins that are widely expressed in the brain, Expression of this channel in Xenopus oocytes resulted in a current that had fast inactivating and noninactivating components, Previously we showed that basal and protein kinase A-induced phosphorylation of the alpha subunit at Ser-446 decreases the fraction of the noninactivating component. In this study we investigated 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 subtype that was inhibited by staurosporine and bisindolylmaleimide but not by calphostin C. However, it was not a PKC-induced phosphorylation 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 coexpressed 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 by activation of metabotropic glutamate receptor fa coupled to a signaling cascade that possibly utilized PKC to induce dephosphorylation and thereby to decrease the extent of inactivation of a KC channel.