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

Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):705-10. doi: 10.1073/pnas.98.2.705. Epub 2001 Jan 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Action Potentials / physiology*
  • Amino Acid Substitution
  • Animals
  • Cell Line
  • DNA, Complementary / genetics
  • Dimerization
  • Genes, src
  • Hippocampus / metabolism
  • Humans
  • Ion Channel Gating / physiology*
  • Ion Transport / physiology
  • Kidney / cytology
  • Kv1.2 Potassium Channel
  • Kv1.4 Potassium Channel
  • Kv1.5 Potassium Channel
  • Macromolecular Substances
  • Models, Biological
  • Mutagenesis, Insertional
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins / metabolism*
  • Oncogene Protein pp60(v-src) / chemistry
  • Oncogene Protein pp60(v-src) / genetics
  • Oocytes
  • Phosphorylation
  • Potassium / physiology
  • Potassium Channels / chemistry
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Potassium Channels, Voltage-Gated*
  • Protein Binding
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-fyn
  • RNA, Messenger / genetics
  • Rabbits
  • Recombinant Fusion Proteins / physiology
  • Transfection
  • Xenopus laevis
  • src Homology Domains / genetics
  • src Homology Domains / physiology*
  • src-Family Kinases / chemistry
  • src-Family Kinases / metabolism*

Substances

  • DNA, Complementary
  • KCNA2 protein, human
  • KCNA4 protein, human
  • KCNA5 protein, human
  • Kv1.2 Potassium Channel
  • Kv1.4 Potassium Channel
  • Kv1.5 Potassium Channel
  • Macromolecular Substances
  • Nerve Tissue Proteins
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • FYN protein, human
  • Oncogene Protein pp60(v-src)
  • Proto-Oncogene Proteins c-fyn
  • src-Family Kinases
  • Potassium