Zolmitriptan stimulates a Ca²⁺-dependent K⁺ current in C6 glioma cells stably expressing recombinant human 5-HT(1B) receptors

Stimulation of a Ca²⁺-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 pD₂ 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 μM), zolmitriptan (1 μM) 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 Ca²⁺-dependent K⁺ channel blockers, iberiotoxin (0.1 μM) 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 Ca²⁺-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. Copyright (C) 2000 Elsevier Science B.V.