Receptor protein tyrosine phosphatase alpha participates in the m1 muscarinic acetylcholine receptor-dependent regulation of Kv1.2 channel activity

The phosphorylation state of a given tyrosine residue is determined by both protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) activ ities. However, little is known about the functional interaction of these o pposing activities at the level of an identified effector molecule. G prote in-coupled receptors (GPCRs), including the mi muscarinic acetylcholine rec eptor (mAChR), regulate a tyrosine kinase activity that phosphorylates and suppresses current generated by the Kv1.2 potassium channel. We examined th e possibility that PTPs also participate in this signaling pathway since th e tyrosine phosphatase inhibitor vanadate increases the extent of both Kv1. 2 phosphorylation and suppression. We show that an endogenous transmembrane tyrosine phosphatase, receptor tyrosine phosphatase alpha (RPTP alpha), be comes tyrosine phosphorylated and co-immunoprecipitates,vith Kv1.2 in a man ner dependent on mi receptor activation, The N- and C-termini of Kv1.2 are shown to bind RPTP alpha irt vitro. Overexpression of RPTP alpha in Xenopus oocytes increases resting Kv1.2 current. Biochemical and electrophysiologi cal analysis reveals that recruiting RPTP alpha to Kv1.2 functionally rever ses the tyrosine kinase-induced phosphorylation and suppression of Kv1.2 cu rrent in mammalian cells. Taken together, these results identify RPTP alpha as a new target of mi mAChR signaling and reveal a novel regulatory mechan ism whereby GPCR-mediated suppression of a potassium channel depends on the coordinate and parallel regulation of PTK and PTP activities.