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

Abstract

Various brain K؉ channels, which may normally exist as complexes of ␣ (pore-forming) and ␤ (auxiliary) subunits, were subjected to regulation by metabotropic glutamate receptors. Kv1.1/Kv␤1.1 is a voltage-dependent K ؉ channel composed of ␣ and ␤ 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 ␣ 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 PKC-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 ␣ 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 1a coupled to a signaling cascade that possibly utilized PKC to induce dephosphorylation and thereby to decrease the extent of inactivation of a K ؉ channel.

Phosphorylation Is Required for Alteration of Kv1.5 K+ Channel Function by the Kvβ1.3 Subunit

“…These data may suggest that complete PKC block is required to shift the activation curve, whereas only a partial block is needed to inhibit inactivation. Alternatively, different PKC isoforms could be involved that show differential inhibitor sensitivity, as has been previously described by other investigators in other systems (23,26,27). Inhibitor peptides that block Ca 2ϩ -dependent PKC isoforms did not alter Kv1.5/Kv␤1.3 interaction (data not shown).…”

Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses

“…The final effector of gintonin-mediated LPAR activation is likely to be the blockade of voltagedependent potassium channels. Previously, it was reported that the PLC-PKC pathway inhibits the action of voltage-dependent potassium channels (Boland and Jackson 1999;Levy et al 1998). In addition, a recent study showed that gintonin application in artificial expressing systems inhibits Kv 1.2 channels .…”

The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in Rodent Models of Anxiety

“…The Group I family includes mGlu1 and mGlu5 receptors; activation of these receptors stimulates phospholipase C, resulting in phosphoinositide hydrolysis and elevation of intracellular Ca 2 þ levels. Group I mGlu receptors have also been shown to modulate ion channels such as K þ channels (Ikeda et al, 1995;Levy et al, 1998), Ca 2 þ channels (Takahashi et al, 1996;McCool et al, 1998), and nonselective cation channels (Zhou and Hablitz, 1997).…”