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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Action Potentials / physiology*
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Amino Acid Substitution
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Animals
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Cell Line
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DNA, Complementary / genetics
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Dimerization
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Genes, src
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Hippocampus / metabolism
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Humans
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Ion Channel Gating / physiology*
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Ion Transport / physiology
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Kidney / cytology
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Kv1.2 Potassium Channel
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Kv1.4 Potassium Channel
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Kv1.5 Potassium Channel
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Macromolecular Substances
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Models, Biological
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Mutagenesis, Insertional
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Mutagenesis, Site-Directed
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Nerve Tissue Proteins / metabolism*
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Oncogene Protein pp60(v-src) / chemistry
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Oncogene Protein pp60(v-src) / genetics
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Oocytes
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Phosphorylation
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Potassium / physiology
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Potassium Channels / chemistry
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Potassium Channels / genetics
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Potassium Channels / metabolism*
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Potassium Channels, Voltage-Gated*
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Protein Binding
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Protein Processing, Post-Translational
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-fyn
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RNA, Messenger / genetics
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Rabbits
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Recombinant Fusion Proteins / physiology
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Transfection
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Xenopus laevis
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src Homology Domains / genetics
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src Homology Domains / physiology*
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src-Family Kinases / chemistry
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src-Family Kinases / metabolism*
Substances
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DNA, Complementary
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KCNA2 protein, human
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KCNA4 protein, human
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KCNA5 protein, human
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Kv1.2 Potassium Channel
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Kv1.4 Potassium Channel
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Kv1.5 Potassium Channel
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Macromolecular Substances
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Nerve Tissue Proteins
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Potassium Channels
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Potassium Channels, Voltage-Gated
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Proto-Oncogene Proteins
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RNA, Messenger
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Recombinant Fusion Proteins
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FYN protein, human
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Oncogene Protein pp60(v-src)
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Proto-Oncogene Proteins c-fyn
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src-Family Kinases
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Potassium