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Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):705-10. Epub 2001 Jan 9.

A mechanism for combinatorial regulation of electrical activity: Potassium channel subunits capable of functioning as Src homology 3-dependent adaptors.

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1
Department of Biology, New York University, New York, NY 10003, USA.

Abstract

It is an open question how ion channel subunits that lack protein-protein binding motifs become targeted and covalently modified by cellular signaling enzymes. Here, we show that Src-family protein tyrosine kinases (PTKs) bind to heteromultimeric Shaker-family voltage-gated potassium (Kv) channels by interactions between the Src homology 3 (SH3) domain and the proline-rich SH3 domain ligand sequence in the Shaker-family subunit Kv1.5. Once bound to Kv1.5, Src-family PTKs phosphorylate adjacent subunits in the Kv channel heteromultimer that lack proline-rich SH3 domain ligand sequences. This SH3-dependent tyrosine phosphorylation contributes to significant suppression of voltage-evoked currents flowing through the heteromultimeric channel. These results demonstrate that Kv1.5 subunits function as SH3-dependent adaptor proteins that marshal Src-family kinases to heteromultimeric potassium channel signaling complexes, and thereby confer functional sensitivity upon coassembled channel subunits that are themselves not bound directly to Src-family kinases by allowing their phosphorylation. This is a mechanism for information transfer between subunits in heteromultimeric ion channels that is likely to underlie the generation of combinatorial signaling diversity in the control of cellular electrical excitability.

PMID:
11149959
PMCID:
PMC14652
DOI:
10.1073/pnas.031446198
[Indexed for MEDLINE]
Free PMC Article

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