K+ channels and the intracellular calcium signal in human melanoma cell proliferation.
K+ channels, membrane voltage, and intracellular free Ca2+ are involved in regulating proliferation in a human melanoma cell line (SK MEL 28). Using patch-clamp techniques, we found an inwardly rectifying K+ channel and a calcium-activated K+ channel. The inwardly rectifying K+ channel was calcium independent, insensitive to charybdotoxin, and carried the major part of the whole-cell current. The K+ channel blockers quinidine, tetraethylammonium chloride and Ba2+ and elevated extracellular K+ caused a dose-dependent membrane depolarization. This depolarization was correlated to an inhibition of cell proliferation. Charybdotoxin affected neither membrane voltage nor proliferation. Basic fibroblast growth factor and fetal calf serum induced a transient peak in intracellular Ca2+ followed by a long-lasting Ca2+ influx. Depolarization by voltage clamp decreased and hyperpolarization increased intracellular Ca2+, illustrating a transmembrane flux of Ca2+ following its electrochemical gradient. We conclude that K+ channel blockers inhibit cell-cycle progression by membrane depolarization. This in turn reduces the driving force for the influx of Ca2+, a messenger in the mitogenic signal cascade of human melanoma cells.
Lepple-Wienhues
A
A
Institut für Klinische Physiologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
Berweck
S
S
Böhmig
M
M
Leo
C P
CP
Meyling
B
B
Garbe
C
C
Wiederholt
M
M
D000818:Animals; D001464:Barium / Q000494:pharmacology; D001790:Blood Physiological Phenomena; D002118:Calcium / Q000502:physiology*; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018999:Charybdotoxin / Q000494:pharmacology; D003470:Culture Media; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D009363:Neoplasm Proteins / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism* / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D003470:Culture Media; D009363:Neoplasm Proteins; D015221:Potassium Channels; D013757:Tetraethylammonium Compounds; D016222:Fibroblast Growth Factor 2; D018999:Charybdotoxin; D001464:Barium; D019789:Tetraethylammonium; D011802:Quinidine; D011188:Potassium; D002118:Calcium