Van Tol H H, Wu C M, Guan H C, Ohara K, Bunzow J R, Civelli O, Kennedy J, Seeman P, Niznik H B, Jovanovic V
Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.
Nature. 1992 Jul 9;358(6382):149-52. doi: 10.1038/358149a0.
The dopamine D4 receptor structurally and pharmacologically resembles the dopamine D2 and D3 receptors. Clozapine, an atypical antipsychotic that is relatively free of the adverse effects of drug-induced parkinsonism and tardive dyskinesia, binds to the D4 receptor with an affinity 10 times higher than to the D2 and D3 receptors. This may explain clozapine's atypical properties. Here we report the existence of at least three polymorphic variations in the coding sequence of the human D4 receptor. A 48-base-pair sequence in the putative third cytoplasmic loop of this receptor exists either as a direct-repeat sequence (D4.2), as a fourfold repeat (D4.4) or as a sevenfold repeat (D4.7). Two more variant alleles were detected in humans. Expression of the complementary DNA for the three cloned receptor variants showed different properties for the long form (D4.7) and the shorter forms (D4.2, D4.4) with respect to clozapine and spiperone binding. To our knowledge, this is the first report of a receptor in the catecholamine receptor family that displays polymorphic variation in the human population. Such variation among humans may underlie individual differences in susceptibility to neuropsychiatric disease and in responsiveness to antipsychotic medication.
多巴胺D4受体在结构和药理学上与多巴胺D2和D3受体相似。氯氮平是一种非典型抗精神病药物，相对没有药物诱发的帕金森症和迟发性运动障碍的不良反应，它与D4受体的结合亲和力比对D2和D3受体高10倍。这可能解释了氯氮平的非典型特性。在此我们报告人类D4受体编码序列中至少存在三种多态性变异。该受体假定的第三个胞质环中的一个48碱基对序列，要么以直接重复序列（D4.2）、四倍重复序列（D4.4）要么以七倍重复序列（D4.7）的形式存在。在人类中还检测到另外两个变异等位基因。三种克隆的受体变异体互补DNA的表达显示，就氯氮平和螺哌隆结合而言，长形式（D4.7）和短形式（D4.2、D4.4）具有不同特性。据我们所知，这是儿茶酚胺受体家族中首个在人类群体中显示多态性变异的受体报告。人类中的这种变异可能是神经精神疾病易感性和抗精神病药物反应性个体差异的基础。
