PH-DEPENDENCE OF LIGAND-BINDING TO D-2 DOPAMINE-RECEPTORS
PH-DEPENDENCE OF LIGAND-BINDING TO D-2 DOPAMINE-RECEPTORS
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DOI：
10.1021/bi00041a044
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发表时间：
1995-10-17
期刊：
影响因子：
2.9
通讯作者：
STRANGE, PG
中科院分区：
文献类型：
--
作者：
DSOUZA, UM;STRANGE, PG
已在 4.5 至 8.5 之间的不同 pH 值下测定了一系列配体与牛尾状核和表达该受体的重组 CHO 细胞中 D-2 多巴胺受体的结合。每个组织中D-2多巴胺受体结合位点的最大数量不受pH变化的影响，但配体与受体结合的亲和力随着pH的降低而降低。对于经典的多巴胺拮抗剂，例如螺哌隆和氟哌啶醇，受体结合解离常数的 pH 依赖性数据表明，受体上单个电离基团的质子化（pK(a) 类似于 6）影响结合过程。对于取代苯甲酰胺类的拮抗剂，数据表明两个电离基团的质子化（pK(a) 在 6 和 7 之间）影响配体结合过程。这些电离残基可能对应于经典拮抗剂的Asp 114以及取代的苯甲酰胺拮抗剂的Asp 114和Asp 80。通过N,N'二环己基碳二亚胺对重组CHO细胞中[H-3]螺哌酮和[H-3]YM 09151-2与D-2受体的结合的抑制，获得了羧基残基参与配体结合过程的进一步证据。
The binding of a range of ligands to D-2 dopamine receptors in bovine caudate nucleus and recombinant CHO cells expressing the receptor has been determined at different pH values between 4.5 and 8.5. The maximum number of D-2 dopamine receptor binding sites in each tissue was not affected by the change in pH, but the affinity of ligands for binding to the receptors was decreased as the pH was decreased. For classical dopamine antagonists, e.g. spiperone and haloperidol, the data on pH dependence of the dissociation constant for receptor binding indicated that the protonation of a single ionizing group on the receptor (pK(a) similar to 6) influenced the binding process. For antagonists of the substituted benzamide class, the data indicated that the protonation of two ionizing groups (pK(a) between 6 and 7) influenced the ligand binding process. These ionizing residues may correspond to Asp 114 for the classical antagonists and Asp 114 and Asp 80 for the substituted benzamide antagonists. Further evidence for the participation of carboxyl residues in the ligand binding process was obtained from the inhibition by N,N'dicyclohexylcarbodiimide of the binding of [H-3]spiperone and [H-3]YM 09151-2 to D-2 receptors in the recombinant CHO cells.