A single amino acid difference accounts for the pharmacological distinctions between the rat and human 5-hydroxytryptamine1B receptors.
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.
Parker
E M
EM
Department of Biophysics, Bristol-Myers Squibb Company, Wallingford, Connecticut 06492.
Grisel
D A
DA
Iben
L G
LG
Shapiro
R A
RA
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D006801:Humans; D020120:Iodocyanopindolol; D016254:Mutagenesis, Insertional; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000378:metabolism
D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D020120:Iodocyanopindolol; C047087:5-carboxamidotryptamine; D010869:Pindolol