A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT_1B receptors

Abstract

NEUROPSYCHIATRIC disorders such as anxiety, depression, migraine, vasospasm and epilepsy may involve different subtypes of the 5-hydroxytryptamine (5-HT) receptor^1,2. The IB subtype, which has a unique pharmacology, was first identified in rodent brain^3–7. But a similar receptor could not be detected in human brain⁶, suggesting the absence in man of a receptor with equivalent function. Recently a human receptor gene was isolated (designated 5-HT_1B receptor^8,9, 5-HT_1Dβ receptor^10,11, or S¹² receptor¹²) which shares 93% identity of the deduced protein sequence with rodent 5-HT_1B receptors^13–15. Although this receptor is identical to rodent 5-HT_1B receptors in binding to 5-HT, it differs profoundly in binding to many drugs. Here we show that replacement of a single amino acid in the human receptor (threonine at residue 355) with a corresponding asparagine found in rodent 5-HT_1B receptors renders the pharmacology of the receptors essentially identical. This demonstrates that the human gene does indeed encode a 1B receptor, which is likely to have the same biological functions as the rodent 5-HT_1B receptor. In addition, these findings show that minute sequence differences between homologues of the same receptor from different species can cause large pharmacological variation. Thus, drug–receptor interactions should not be extrapolated from animal to human species without verification.