MODULATION OF THE KV1.3 POTASSIUM CHANNEL BY RECEPTOR TYROSINE KINASES

The voltage-dependent potassium channel, Kv1.3, is modulated by the ep idermal growth factor receptor (EGFr) and the insulin receptor tyrosin e kinases. When the EGFr and Kv1.3 are coexpressed in HEK 293 cells, a cute treatment of the cells with EGF during a patch recording can supp ress the Kv1.3 current within tens of minutes. This effect appears to be due to tyrosine phosphorylation of the channel, as it is blocked by treatment with the tyrosine kinase inhibitor erbstatin, or by mutatio n of the tyrosine at channel amino acid position 479 to phenylalanine. Previous work has shown that there is a large increase in the tyrosin e phosphorylation of Kv1.3 when it is coexpressed with the EGFr. Pretr eatment of EGFr and Kv1.3 cotransfected cells with EGF before patch re cording also results in a decrease in peak Kv1.3 current. Furthermore, pretreatment of cotransfected cells with an antibody to the EGFr liga nd binding domain (alpha-EGFr),which blocks receptor dimerization and tyrosine kinase activation, blocks the EGFr-mediated suppression of Kv 1.3 current. Insulin treatment during patch recording also causes an i nhibition of Kv1.3 current after tens of minutes, while pretreatment f or 18 h produces almost total suppression of current. In addition to d epressing peak Kv1.3 current, EGF treatment produces a speeding of C-t ype inactivation, while pretreatment with the alpha-EGFr slows C-type inactivation. In contrast, insulin does not influence C-type inactivat ion kinetics. Mutational analysis indicates that the EGF-induced modul ation of the inactivation rate occurs by a mechanism different from th at of the EGF-induced decrease in peak current. Thus, receptor tyrosin e kinases differentially modulate the current magnitude and kinetics o f a voltage-dependent potassium channel.