A Single Amino Acid Difference Accounts for the Pharmacological Distinctions Between the Rat and Human 5‐Hydroxytryptamine1B Receptors

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Abstract
Molecular cloning of the rat and human 5‐hydroxytryptamine1B (5‐HT1B) receptors has revealed that the primary amino acid sequence of these two receptors is >90% identical. Despite this high degree of primary sequence homology, these two receptors have significantly different pharmacological properties. A mutant human 5‐HT1B receptor was constructed in which Thr355 was replaced by Asn, the corresponding residue at this position in the rat 5‐HT1B receptor. The pharmacology of the mutant human 5‐HT1B receptor was very similar to that of the rat 5‐HT1B receptor. Specifically, the mutant receptor had much higher affinity for pindolol, [125I]‐iodocyanopindolol, propranolol, and CP‐93,129 than the wild‐type receptor. In contrast, the mutant had significantly lower affinity for sumatriptan, N,N‐dipropyl‐5‐carboxamidotryptamine, 5‐methoxy‐N,N‐dimethyltryptamine, methysergide, metergoline, and rauwolscine. These data suggest that a single amino acid difference at position 355 is responsible for the pharmacological differences between the rat and human 5‐HT1B receptors.