A SINGLE AMINO-ACID DIFFERENCE CONFERS MAJOR PHARMACOLOGICAL VARIATION BETWEEN HUMAN AND RODENT 5-HT(1B) RECEPTORS

NEUROPSYCHIATRIC disorders such as anxiety, depression, migraine, vasospasm and epilepsy may involve different subtypes of the 5-hydroxytryptamine (5-HT) receptor1,2. The 1B subtype, which has a unique pharmacology, was first identified in rodent brain3-7. 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-HT1B receptor8,9, 5-HT1Dbeta receptor10,11, or S12 receptor12) which shares 93% identity of the deduced protein sequence with rodent 5-HT1B receptors13-15. Although this receptor is identical to rodent 5-HT1B 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-HT1B 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-HT1B 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.