A mechanism for combinatorial regulation of electrical activity: Potassium channel subunits capable of functioning as Src homology 3-dependent adaptors.
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.
Mesh Terms:
Action Potentials, Amino Acid Substitution, Animals, Cell Line, DNA, Complementary, Dimerization, Genes, src, Hippocampus, Humans, Ion Channel Gating, Ion Transport, Kidney, Kv1.2 Potassium Channel, Kv1.4 Potassium Channel, Kv1.5 Potassium Channel, Macromolecular Substances, Models, Biological, Mutagenesis, Insertional, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Oncogene Protein pp60(v-src), Oocytes, Phosphorylation, Potassium, Potassium Channels, Potassium Channels, Voltage-Gated, Protein Binding, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-fyn, RNA, Messenger, Rabbits, Recombinant Fusion Proteins, Transfection, Xenopus laevis, src Homology Domains, src-Family Kinases
Action Potentials, Amino Acid Substitution, Animals, Cell Line, DNA, Complementary, Dimerization, Genes, src, Hippocampus, Humans, Ion Channel Gating, Ion Transport, Kidney, Kv1.2 Potassium Channel, Kv1.4 Potassium Channel, Kv1.5 Potassium Channel, Macromolecular Substances, Models, Biological, Mutagenesis, Insertional, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Oncogene Protein pp60(v-src), Oocytes, Phosphorylation, Potassium, Potassium Channels, Potassium Channels, Voltage-Gated, Protein Binding, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-fyn, RNA, Messenger, Rabbits, Recombinant Fusion Proteins, Transfection, Xenopus laevis, src Homology Domains, src-Family Kinases
Proc. Natl. Acad. Sci. U.S.A.
Date: Jan. 16, 2001
PubMed ID: 11149959
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