Zolmitriptan stimulates a Ca(2+)-dependent K(+) current in C6 glioma cells stably expressing recombinant human 5-HT(1B) receptors.
Stimulation of a Ca(2+)-dependent K(+) current by zolmitriptan, a 5-HT(1B/1D) receptor partial agonist, was investigated in C6 glioma cells stably expressing recombinant human 5-HT(1B) receptors. Outward K(+) currents (I(K)) were examined in non-transfected C6 glioma cells and in cells expressing cloned human 5-HT(1B) receptors using the patch-clamp technique in the whole-cell configuration. In C6 glioma cells expressing recombinant human 5-HT(1B) receptor, zolmitriptan increased I(K) in a concentration-dependent manner (maximum increase 16.3+/-7.8%, n=5, p<0.001) with a pD(2) value (geometric mean with 95% confidence intervals) of 7.03 (7.90-6.10). Zolmitriptan failed to elicit increases in I(K) in non-transfected C6 cells. In the presence of the mixed 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2(-methyl-4(5-methyl-1 ,2,4)-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide 2HCl (GR 127935, 0. 1 mcM), zolmitriptan (1 mcM) failed to significantly increase I(K) in C6 cells expressing human 5-HT(1B) receptors confirming that zolmitriptan-evoked responses were indeed mediated by human 5-HT(1B) receptors. In C6 cells expressing cloned human 5-HT(1B) receptors, zolmitriptan-induced increases in I(K) were prevented by the calcium chelator, EGTA (5 mM) when included in the patch pipette (maximum increase -3.3+/-4.2%, n=4, P=NS). The Ca(2+)-dependent K(+) channel blockers, iberiotoxin (0.1 mcM) and tetraethylammonium (TEA, 1 mM), abolished zolmitriptan-induced increases in I(K) (4.5+/-7.3%, n=4 and -0.8+/-1.7%, n=4, respectively, P=NS in each case) in C6 cells expressing human 5-HT(1B) receptors, confirming the involvement of Ca(2+)-dependent K(+) channels. In conclusion, the 5-HT(1B/1D) receptor partial agonist, zolmitriptan, stimulates I(K/Ca) in C6 glioma cells stably transfected with human 5-HT(1B) receptors suggesting an increase of hyperpolarizing current.
Le Grand
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B
Division of Cardiovascular Diseases, Centre de Recherche Pierre Fabre, 17 Av. Jean Moulin, 81106 Cedex, Castres, France.
Panissié
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A
Perez
M
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Pauwels
P J
PJ
John
G W
GW
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology*; D023303:Oxazolidinones; D010455:Peptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D019789:Tetraethylammonium / Q000494:pharmacology; D014363:Tryptamines; D014407:Tumor Cells, Cultured
C470302:HTR1B protein, human; D010069:Oxadiazoles; D010080:Oxazoles; D023303:Oxazolidinones; D010455:Peptides; D010879:Piperazines; D015221:Potassium Channels; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D011993:Recombinant Fusion Proteins; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan; C090701:GR 127935; D019789:Tetraethylammonium; C064719:iberiotoxin; D002118:Calcium