Modulation of potassium channels by protein tyrosine kinase inhibitors.
Exposure of non-excitatory cells to the tyrosine kinase (PTK) inhibitors, genistein, herbimycin A, and tyrphostin, induced at least two families of K+ currents. The first, a TEA-insensitive slow-inactivating K+ current, is induced within 3 min following treatment with 140 mM genistein or 100 nM herbimycin A. The second current, a TEA-sensitive delayed rectifier, is induced within 30 min following treatment with 50 mM genistein or 10 nM herbimycin A. Currents with similar biophysical and pharmacological characteristics are induced in these cells following exposure to ionizing radiation. The radiation-induced currents are inhibited by pretreatment with the free radical scavenger, N-Acetyl L-Cysteine, or by pretreatment with the protein kinase C inhibitor, staurosporine; those induced by PTK inhibitors are not. The latter, therefore, do not appear to be mediated through free radicals or require serine/threonine phosphorylation for activation. Once the channels are activated by the PTK inhibitors, phosphorylation of the channel at serine/threonine residues results in slower inactivation of the induced current. We propose that protein tyrosine phosphorylation of the K+ channel protein itself or of a factor that interacts with it maintains the K+ channels of non-excitatory cells in a closed state. Following exposure to ionizing radiation, free radical-induced activation of serine/threonine kinase(s) results in phosphorylation of the channel and/or inactivation of a tyrosine kinase that in turn leads to activation of the K+ channels.
Saad
A H
AH
Department of Radiation Oncology, Stanford University School of Medicine, California 94305-5468.
Kuo
S S
SS
Koong
A C
AC
Hahn
G M
GM
Giaccia
A J
AJ
D000111:Acetylcysteine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000595:Amino Acid Sequence; D016227:Benzoquinones; D002118:Calcium / Q000494:pharmacology; D002460:Cell Line; D004553:Electric Conductivity; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D047029:Lactams, Macrocyclic; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D019311:Staurosporine
D000470:Alkaloids; D016227:Benzoquinones; D016166:Free Radical Scavengers; D047029:Lactams, Macrocyclic; D010750:Phosphoproteins; D015221:Potassium Channels; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D019311:Staurosporine; D002118:Calcium; D000111:Acetylcysteine