A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT1B receptors

Nature. 1992 Nov 12;360(6400):161-3. doi: 10.1038/360161a0.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alprenolol / pharmacology
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Dihydroergotamine / metabolism
  • Humans
  • In Vitro Techniques
  • Methiothepin / metabolism
  • Methysergide / metabolism
  • Mice
  • Molecular Sequence Data
  • Pindolol / metabolism
  • Propranolol / metabolism
  • Rats
  • Receptors, Serotonin / chemistry*
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism
  • Serotonin Receptor Agonists / metabolism


  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Serotonin
  • Dihydroergotamine
  • Methiothepin
  • Alprenolol
  • Propranolol
  • Pindolol
  • Methysergide