Constitutive activation of delayed-rectifier potassium channels by a src family tyrosine kinase in Schwann cells.
In the nervous system, Src family tyrosine kinases are thought to be involved in cell growth, migration, differentiation, apoptosis, as well as in myelination and synaptic plasticity. Emerging evidence indicates that K+ channels are crucial targets of Src tyrosine kinases. However, most of the data accumulated so far refer to heterologous expression, and native K+-channel substrates of Src or Fyn in neurons and glia remain to be elucidated. The present study shows that a Src family tyrosine kinase constitutively activates delayed-rectifier K+ channels (IK) in mouse Schwann cells (SCs). IK currents are markedly downregulated upon exposure of cells to the tyrosine kinase inhibitors herbimycin A and genistein, while a potent upregulation of IK is observed when recombinant Fyn kinase is introduced through the patch pipette. The Kv1.5 and Kv2.1 K+-channel alpha subunits are constitutively tyrosine phosphorylated and physically associate with Fyn both in cultured SCs and in the sciatic nerve in vivo. Kv2.1- channel subunits are found to interact with the Fyn SH2 domain. Inhibition of Schwann cell proliferation by herbimycin A and by K+-channel blockers suggests that the functional linkage between Src tyrosine kinases and IK channels could be important for Schwann cell proliferation and the onset of myelination.
Neurobiology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
A
A
Sobko
A
A
Peretz
B
B
Attali
D000818:Animals; D016227:Benzoquinones; D002455:Cell Division; D002478:Cells, Cultured; D051668:Delayed Rectifier Potassium Channels; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D015640:Ion Channel Gating; D047029:Lactams, Macrocyclic; D051379:Mice; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D051076:Proto-Oncogene Proteins c-fyn; D011809:Quinones / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D012583:Schwann Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D012584:Sciatic Nerve / Q000196:embryology / Q000378:metabolism; D051669:Shab Potassium Channels; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016227:Benzoquinones; D051668:Delayed Rectifier Potassium Channels; D004791:Enzyme Inhibitors; C496990:Kcnb1 protein, mouse; D047029:Lactams, Macrocyclic; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011518:Proto-Oncogene Proteins; D011809:Quinones; D011994:Recombinant Proteins; D051669:Shab Potassium Channels; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D019833:Genistein; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases