A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT1B receptors.
Neuropsychiatric disorders such as anxiety, depression, migraine, vasospasm and epilepsy may involve different subtypes of the 5-hydroxytryptamine (5-HT) receptor. The 1B subtype, which has a unique pharmacology, was first identified in rodent brain. But a similar receptor could not be detected in human brain, suggesting the absence in man of a receptor with equivalent function. Recently a human receptor gene was isolated (designated 5-HT1B receptor, 5-HT1D beta receptor, or S12 receptor) which shares 93% identity of the deduced protein sequence with rodent 5-HT1B receptors. 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.
Oksenberg
D
D
Department of Pulmonary Research and Gene Therapy, Genentech Inc., South San Francisco, California 94080.
Marsters
S A
SA
O'Dowd
B F
BF
Jin
H
H
Havlik
S
S
Peroutka
S J
SJ
Ashkenazi
A
A
D000526:Alprenolol / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004087:Dihydroergotamine / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008719:Methiothepin / Q000378:metabolism; D008784:Methysergide / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010869:Pindolol / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000378:metabolism
D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D004087:Dihydroergotamine; D008719:Methiothepin; D000526:Alprenolol; D011433:Propranolol; D010869:Pindolol; D008784:Methysergide