期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 421, 期 2, 页码 69-76出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/S0014-2999(01)01027-5
关键词
5-HT; 5-Hydroxytryptamine; 5-HT1B receptor; site-directed mutagenesis; GR125743
The antagonist radioligand [H-3]GR125743 and the agonist radioligand [H-3]5-HT were used to investigate the pharmacological characteristics of the G protein uncoupled agonist low-affinity and G protein coupled agonist high-affinity conformations of the wild-type and mutant human 5-hydroxytryptamine(1B) (5-HT1B) receptors. We found that substitution of phenylalanine 185 in transmembrane region IV by alanine or methionine resulted in a reduced number of receptors in the coupled conformation, as well as a reduced affinity of 5-HT for the uncoupled conformation. In contrast, substitution of phenylalanine 331 in transmembrane region VI by alanine increased the affinity of 5-HT for the uncoupled conformation 11-fold thus reducing the agonist low-affinity to agonist high-affinity (K-il/K-ih) ratio 5-fold. This reduced ratio was correlated with a significantly reduced intrinsic activity of 5-HT previously determined by its ability to inhibit forskolin-stimulated cAMP production. In conclusion, these results show that single amino acid substitutions can selectively change the affinity of 5-HT for the G protein uncoupled conformation of the 5-HT1B receptor and alter the intrinsic activity of the ligand. (C) 2001 Elsevier Science B.V. All rights reserved.
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