Sorenson E M, Gallagher J P
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, USA.
J Pharmacol Exp Ther. 1996 Jun;277(3):1733-43.
The pharmacology, calcium dependence and G protein mediation of the membrane hyperpolarization of rat dorsolateral septal nucleus (DLSN) neurons in response to nicotinic agonists was examined to classify the nicotinic receptor mediating the response. Intracellular recording from DSLN neurons in a brain slice preparation was used to determine whether chlorisondamine, trimethaphan, cytisine or strychnine inhibited the membrane hyperpolarization in response to application of the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP). Chlorisondamine was found to block the response only at a high concentration (500 microM) although strychnine (100 microM) was without effect. Cytisine was neither an effective agonist nor an antagonist (500 microM). Surprisingly, trimethaphan appeared to act as an agonist, rather than an antagonist, with a potency and efficacy similar to that reported for nicotine at this receptor. The response was dependent on intracellular calcium stores because it persisted in the absence of extracellular calcium but was blocked by intracellular injection of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Injection of GTP gamma S into the neurons blocked the nicotinic response. Apamin, iberiotoxin and charybdotoxin reduced but did not block the response at concentrations that selectively block calcium-dependent potassium channels. These results indicate that the nicotinic response in DLSN neurons may be mediated by a metabotropic nicotinic receptor coupled to a calcium-dependent potassium channel through the activation of a G-protein and release of intracellular calcium stores. The unusual pharmacology of the nicotinic receptor on DLSN neurons indicates that it may be a novel receptor which has yet to be cloned.
研究了大鼠背外侧隔核（DLSN）神经元对烟碱激动剂产生膜超极化反应的药理学特性、钙依赖性和G蛋白介导作用，以对介导该反应的烟碱受体进行分类。采用脑片制备中DLSN神经元的细胞内记录法，来确定氯筒箭毒碱、三甲噻芬、金雀花碱或士的宁是否能抑制对烟碱激动剂1,1 - 二甲基 - 4 - 苯基哌嗪鎓（DMPP）应用所产生的膜超极化。发现氯筒箭毒碱仅在高浓度（500微摩尔）时阻断反应，而士的宁（100微摩尔）无作用。金雀花碱既不是有效的激动剂也不是拮抗剂（500微摩尔）。令人惊讶的是，三甲噻芬似乎表现为激动剂而非拮抗剂，其效力和效能与该受体上尼古丁的报道相似。该反应依赖于细胞内钙库，因为在无细胞外钙的情况下反应持续存在，但通过细胞内注射1,2 - 双（2 - 氨基苯氧基）乙烷 - N,N,N',N' - 四乙酸（BAPTA）可阻断。向神经元注射GTPγS可阻断烟碱反应。蜂毒明肽、iberiotoxin和大蝎毒素在选择性阻断钙依赖性钾通道的浓度下可降低但不阻断反应。这些结果表明，DLSN神经元中的烟碱反应可能由一种代谢型烟碱受体介导，该受体通过激活G蛋白和释放细胞内钙库与钙依赖性钾通道偶联。DLSN神经元上烟碱受体不同寻常的药理学特性表明它可能是一种尚未被克隆的新型受体。
