Paul I A, Basile A S, Rojas E, Youdim M B, De Costa B, Skolnick P, Pollard H B, Kuijpers G A
Laboratory of Neuroscience, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
FASEB J. 1993 Sep;7(12):1171-8. doi: 10.1096/fasebj.7.12.8375616.
Neither the physiological function of sigma (sigma) receptors nor the cellular mechanism responsible for the pharmacological effects of sigma receptor ligands is known. We now report that sigma receptor ligands noncompetitively inhibit nicotine-stimulated catecholamine release from bovine adrenal chromaffin cells in a concentration-dependent and reversible manner. The rank order of potency of ligands to inhibit nicotine-stimulated catecholamine release is significantly correlated (P < 0.005) with that observed in radioligand binding assays selective for the sigma 1 receptor subtype. This naltrexone-insensitive effect is paralleled by an inhibition of nicotine-stimulated increases in [Ca2+]i. Sigma ligands were without effect on catecholamine release or [Ca2+]i in the absence of nicotine. In addition, nicotine accelerated the association of the sigma receptor selective radioligand, 3Hpentazocine, to adrenal medullary homogenates while having no effect on the rate of ligand dissociation, consistent with a sigma ligand binding site closely associated with and allosterically modulated by the nicotinic acetylcholine receptor. Thus, the actions of agonists at the nicotinic acetylcholine receptor in bovine chromaffin cells are modulated by sigma 1 receptor selective ligands.
σ受体的生理功能以及导致σ受体配体产生药理作用的细胞机制均尚不明确。我们现在报告，σ受体配体以浓度依赖性和可逆的方式非竞争性抑制尼古丁刺激的牛肾上腺嗜铬细胞中儿茶酚胺的释放。配体抑制尼古丁刺激的儿茶酚胺释放的效力顺序与在对σ1受体亚型具有选择性的放射性配体结合试验中观察到的顺序显著相关（P < 0.005）。这种对纳曲酮不敏感的效应与抑制尼古丁刺激的细胞内钙离子浓度（[Ca2+]i）升高相平行。在没有尼古丁的情况下，σ配体对儿茶酚胺释放或[Ca2+]i没有影响。此外，尼古丁加速了σ受体选择性放射性配体3H喷他佐辛与肾上腺髓质匀浆的结合，而对配体解离速率没有影响，这与一个与烟碱型乙酰胆碱受体紧密相关并受其变构调节的σ配体结合位点一致。因此，牛嗜铬细胞中烟碱型乙酰胆碱受体激动剂的作用受到σ1受体选择性配体的调节。
