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Next Article 
Journal of Neuroscience, Vol 16, 1581-1590, Copyright © 1996 by Society for Neuroscience
Tyrosine phosphorylation of the Kv1.3 potassium channel
TC Holmes, DA Fadool and IB Levitan
Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts 02254, USA.
Kv1.3, a voltage-dependent potassium channel cloned from mammalian brain
and T lymphocytes, contains multiple tyrosine residues that are putative
targets for tyrosine kinases. We have examined the tyrosine phosphorylation
of Kv1.3, expressed transiently in human embryonic kidney (or HEK) 293
cells, by endogenous and coexpressed tyrosine kinases. Tyrosine
phosphorylation is measured by a strategy of immunoprecipitation followed
by. Western blot analysis, using antibodies that specifically recognize
Kv1.3 and phosphotyrosine. Coexpression of the constitutively active
tyrosine kinase v-src, together with Kv1.3, causes a large increase in the
tyrosine phosphorylation of the channel protein. This phosphorylation of
Kv1.3 can be reversed by treatment with alkaline phosphatase before Western
blot analysis. Coexpression with a receptor tyrosine kinase, the human
epidermal growth factor receptor, also causes an increase in tyrosine
phosphorylation of Kv1.3. The effects of endogenous tyrosine kinases were
examined by treating Kv1.3-transfected cells with the specific
membrane-permeant tyrosine phosphatase inhibitor pervanadate. Pervanadate
treatment causes a time- and concentration-dependent increase in the
tyrosine phosphorylation of Kv1.3. This increased tyrosine phosphorylation
of Kv1.3 is accompanied by a time-dependent decrease in Kv1.3 current,
measured by patch-clamp analysis with cell- attached membrane patches. The
pervanadate-induced suppression of current and much of the channel tyrosine
phosphorylation are eliminated by mutation of a specific tyrosine residue,
at position 449 of Kv1.3, to phenylalanine. Thus, there is a continual
phosphorylation and dephosphorylation of Kv1.3 by endogenous kinases and
phosphatases, and perturbation of this constitutive
phosphorylation/dephosphorylation cycle can profoundly influence channel
activity.
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