Plassat J L, Amlaiky N, Hen R
Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, U/184 de l'INSERM, Département de Neurobiologie, Faculté de Médecine, Strasbourg, France.
Mol Pharmacol. 1993 Aug;44(2):229-36.
Serotonin modulates a wide range of physiological functions by activating multiple receptors, which are coupled to various effector systems. Using a strategy based on amino acid sequence homology between 5-hydroxytryptamine (5-HT) receptors, we have isolated from a mouse brain library a cDNA encoding a new 5-HT receptor, 5-HTx, that activates adenylate cyclase. Amino acid sequence comparisons revealed that the 5-HTx receptor was a distant relative of previously cloned 5-HT receptors, with the highest percentage of homology (42%) being with the 5-HTdro1 receptor, a Drosophila 5-HT receptor positively coupled to adenylate cyclase. In COS-7 cells transiently expressing the 5-HTx receptor, 5-HT induced an increase in cAMP levels that was dose dependent and saturable (EC50 = 45 nM). Agonists displayed the following rank order of potencies: 5-carboxamidotryptamine > 5-methoxytryptamine > 5-HT > RU 24969 > 8-hydroxy-2-(di-n-propylamino)tetralin. The most efficient antagonists in inhibiting the stimulatory effect of 5-HT were methysergide, methiothepin, mesulergine, metergoline, clozapine, ergotamine, and (+)-butaclamol. Membranes of COS-7 cells expressing the 5-HTx receptor displayed a single saturable binding site for [3H]5-HT. The order of potencies of various drugs in displacing [3H]5-HT binding was similar to the order obtained in cAMP experiments. The pharmacological profile of this receptor does not correspond to the profile of any of the classic 5-HT receptor subtypes. Expression of 5-HTx mRNA was highest in brainstem and lower in forebrain, cerebellum, intestine, and heart. The 5-HTx receptor might therefore correspond to 5-HT1-like receptors that have been shown to induce relaxation in porcine vena cava and guinea pig ileum as well as tachycardia in cat heart. The high affinity of the 5-HTx receptor for neuroleptic agents such as (+)-butaclamol and clozapine suggests also that this receptor might play a role in certain neuropsychiatric disorders.
血清素通过激活多种与不同效应系统偶联的受体来调节广泛的生理功能。利用基于5-羟色胺（5-HT）受体之间氨基酸序列同源性的策略，我们从小鼠脑文库中分离出一个编码新的5-HT受体5-HTx的cDNA，该受体可激活腺苷酸环化酶。氨基酸序列比较显示，5-HTx受体是先前克隆的5-HT受体的远亲，与果蝇中与腺苷酸环化酶正偶联的5-HTdro1受体同源性最高（42%）。在瞬时表达5-HTx受体的COS-7细胞中，5-HT诱导cAMP水平升高，呈剂量依赖性且可饱和（EC50 = 45 nM）。激动剂的效力顺序如下：5-羧酰胺色胺>5-甲氧基色胺>5-HT>RU 24969>8-羟基-2-（二正丙基氨基）四氢萘。抑制5-HT刺激作用最有效的拮抗剂是麦角新碱、甲硫噻平、美舒麦角、米替戈林、氯氮平、麦角胺和（+）-布他拉莫。表达5-HTx受体的COS-7细胞膜显示出一个单一的可饱和[3H]5-HT结合位点。各种药物取代[3H]5-HT结合的效力顺序与cAMP实验中得到的顺序相似。该受体的药理学特征与任何经典的5-HT受体亚型均不相符。5-HTx mRNA在脑干中的表达最高，在前脑、小脑、肠道和心脏中的表达较低。因此，5-HTx受体可能对应于已被证明能诱导猪腔静脉和豚鼠回肠舒张以及猫心脏心动过速的5-HT1样受体。5-HTx受体对诸如（+）-布他拉莫和氯氮平之类的抗精神病药物具有高亲和力，这也表明该受体可能在某些神经精神疾病中起作用。
