5-羟色胺在5-HT2受体上激动剂解离常数估计值的差异：急性脱敏问题？

Differences in agonist dissociation constant estimates for 5-HT at 5-HT2-receptors: a problem of acute desensitization?

作者信息

Leff P, Martin G R

机构信息

Department of Pharmacology (I), Wellcome Research Laboratories, Beckenham, Kent.

出版信息

Br J Pharmacol. 1988 Oct;95(2):569-77. doi: 10.1111/j.1476-5381.1988.tb11678.x.

DOI:10.1111/j.1476-5381.1988.tb11678.x

PMID:3228675

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1854157/

Abstract

The agonist dissociation constant for 5-hydroxytryptamine (5-HT) was estimated in the guinea-pig isolated trachea by the method of receptor inactivation. The value obtained (pKA = 6.45) was significantly lower than estimates previously obtained in the rabbit aorta and rat jugular vein, although all three tissues are supposed to contain the same 5-HT2 class of receptor. 2. The antagonist dissociation constant for alpha,alpha-dimethyltryptamine was also estimated in the guinea-pig trachea. The pKB value (5.43) was not significantly different from previous estimates in the rabbit aorta and rat jugular vein, consistent with receptor homogeneity between the three tissues. 3. The effect-time profiles corresponding to individual 5-HT applications were more transient in the guinea-pig trachea than in the rabbit aorta. This difference could be accounted for using a simple model of acute receptor desensitization (Leff, 1986), assuming that the conversion of active agonist-receptor complexes into inactive ones was faster in the guinea-pig trachea than in the rabbit aorta. 4. Computer simulation of the desensitization model showed that the discrepancy of pKA estimates for 5-HT between the rabbit aorta and guinea-pig trachea could also be explained using the same rate constant difference that accounted for the difference in effect-time profiles. This analysis indicated that the estimate made in the trachea was erroneously low, whereas that made in the aorta was concluded to be correct. 5. The apparent association between transience of response and pKA estimates is discussed with particular attention to the reliability of agonist affinity estimates in receptor classification.

摘要

通过受体失活法在豚鼠离体气管中估算了5-羟色胺（5-HT）的激动剂解离常数。得到的值（pKA = 6.45）显著低于先前在兔主动脉和大鼠颈静脉中获得的估算值，尽管这三种组织都被认为含有相同的5-HT2类受体。2. 还在豚鼠气管中估算了α,α-二甲基色胺的拮抗剂解离常数。pKB值（5.43）与先前在兔主动脉和大鼠颈静脉中的估算值无显著差异，这与三种组织之间的受体同质性一致。3. 在豚鼠气管中，与单次5-HT应用相对应的效应-时间曲线比在兔主动脉中更短暂。假设活性激动剂-受体复合物向无活性复合物的转化在豚鼠气管中比在兔主动脉中更快，那么使用急性受体脱敏的简单模型（Leff，1986）可以解释这种差异。4. 脱敏模型的计算机模拟表明，兔主动脉和豚鼠气管之间5-HT的pKA估算值差异也可以用解释效应-时间曲线差异的相同速率常数差异来解释。该分析表明，在气管中得到的估算值错误地偏低，而在主动脉中得到的估算值被认为是正确的。5. 讨论了反应短暂性与pKA估算值之间的明显关联，特别关注受体分类中激动剂亲和力估算的可靠性。