Omega-Agatoxin IVA blocks nicotinic receptor channels in bovine chromaffin cells

Departamento de Farmacología, Universidad de Alicante, Spain.
FEBS Letters (Impact Factor: 3.17). 04/1995; 362(1):15-8. DOI: 10.1016/0014-5793(95)00149-4
Source: PubMed


We have studied the contribution of P-type voltage-dependent Ca2+ channels to both catacholamine (CA) and ATP secretion from bovine chromaffin cells induced by high K+ or nicotine using omega-agatoxin IVA, a selective blocker of P-type voltage-dependent Ca2+ channels. We found that high K+ (75 mM) induced the release of about 13% of norepinephrine, 5% epinephrine and 11% ATP, and that omega-agatoxin (100 nM) did not affect this secretion. However, both nicotine-induced CA and ATP secretion were significantly blocked (about 50%) by omega-agatoxin IVA (100 nM). In addition, this toxin also reversibly blocked (about 70%) the inward current induced by nicotine in bovine chromaffin cells. The results suggest that, besides its known action of blocking P-type voltage-dependent channels, omega-agatoxin is a potent and reversible blocker of the nicotinic receptor channel in chromaffin cells, and that this action would explain the blockade of nicotine-induced secretion.

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Available from: Carmen González-García, Jun 20, 2014

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    ABSTRACT: The effects of omega-toxins and various Ca2+ antagonist subtypes on the 45Ca2+ entry into bovine adrenal medullary chromaffin cells stimulated via nicotinic acetylcholine receptors or via direct depolarization with K+, have been compared. The conditions selected to stimulate the 45Ca2+ entry consisted of a 60-s period of exposure of cells to 100 microM of the nicotinic acetylcholine receptor agonist dimethylphenylpiperazinium or to 70 mM K+. The N-type voltage-dependent Ca2+ channel blockers omega-conotoxin GVIA and MVIIA (1 microM) inhibited 45Ca2+ entry stimulated by dimethylphenylpiperazinium or K+ by around 25-30%. The P-type Ca2+ channel blocker omega-agatoxin IVA (10 nM) did not affect the dimethylphenylpiperazinium nor the K+ responses; 1 microM (Q-channel blockade) inhibited both responses by around 50%. The N/P/Q-type Ca2+ channel blocker omega-contoxin MVIIC (1 microM) inhibited the K+ evoked 45Ca2+ entry by 70%, while dimethylphenylpiperazinium was blocked by 50% (P < 0.001). The L-type Ca2+ channel blockers nifedipine, furnidipine, diltiazem or verapamil (3 microM each) inhibited much more the dimethylphenylpiperazinium than the K+ response. The dimethylphenylpiperazinium signal was blocked 71, 88, 89, and 53%, respectively, by nifedipine, furnidipine, diltiazem and verapamil, and the K+ response by 38, 29, 22, and 10%. Combined omega-conotoxin MVIIC (1 microM) and furnidipine (3 microM) blocked 100% of the K+ evoked 45Ca2+ entry. However, combined omega-conotoxin GVIA (1 microM), and furnidipine left unblocked 50% of the K+ response. The "wide spectrum' Ca2+ channel antagonists flunarizine or dotarizine (3 microM each) blocked the dimethylphenylpiperazinium and the K+ responses to a similar extent (50%); cinnarizine (3 microM) inhibited more the dimethylphenylpiperazinium (82%) than the K+ response (21%). At 3 microM, the highly lipophilic beta-adrenoceptor antagonist (+/-)-propranolol, reduced by 68% the dimethylphenylpiperazinium signal and by 23% the K+ signal. Other high lipophilic beta-adrenoceptor antagonists such as metoprolol and labetalol, reduced little the dimethylphenylpiperazinium and the K+ responses. The highly lipophilic agent penfluridol blocked the dimethylpiperazinium response by 30% and the K+ response by 50%. One of the least lipophilic compounds tested, (+)-lubeluzole, blocked by 40% the dimethylphenylpiperazinium and the K+ responses. These data are compatible with the idea that the various omega-toxin peptides used to separate pharmacologically the different voltage-dependent Ca2+ channels expressed by neurones, do not block the neuronal nicotinic acetylcholine receptor ion channel. In contrast the L-type Ca2+ channel blockers do block the nicotinic acetylcholine receptor ionophore. Lipophilicity of the compounds is not a requirement for Ca2+ channel or nicotinic acetylcholine receptor blockade.
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