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.
Nitabach
M N
MN
Department of Biology, New York University, New York, NY 10003, USA.
Llamas
D A
DA
Araneda
R C
RC
Intile
J L
JL
Thompson
I J
IJ
Zhou
Y I
YI
Holmes
T C
TC
D000200:Action Potentials / Q000502:physiology*; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D019281:Dimerization; D016391:Genes, src; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D017136:Ion Transport / Q000502:physiology; D007668:Kidney / Q000166:cytology; D051663:Kv1.2 Potassium Channel; D051665:Kv1.4 Potassium Channel; D051666:Kv1.5 Potassium Channel; D046911:Macromolecular Substances; D008954:Models, Biological; D016254:Mutagenesis, Insertional; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015688:Oncogene Protein pp60(v-src) / Q000737:chemistry / Q000235:genetics; D009865:Oocytes; D010766:Phosphorylation; D011188:Potassium / Q000502:physiology; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014982:Xenopus laevis; D018909:src Homology Domains / Q000235:genetics / Q000502:physiology*; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism*
D018076:DNA, Complementary; C496969:KCNA2 protein, human; C496977:KCNA4 protein, human; C496981:KCNA5 protein, human; D051663:Kv1.2 Potassium Channel; D051665:Kv1.4 Potassium Channel; D051666:Kv1.5 Potassium Channel; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C494957:FYN protein, human; D015688:Oncogene Protein pp60(v-src); D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D011188:Potassium