title: Two amino acid differences in the sixth transmembrane domain are partially responsible for the pharmacological differences between the 5-HT1D beta and 5-HT1E 5-hydroxytryptamine receptors.
abstract: 5-Hydroxytryptamine elicits its physiological effects by interacting with a diverse group of receptors. Two of these receptors, the 5-HT1D beta and the 5-HT1E receptors, are approximately 60% identical in the transmembrane domains that presumably form the ligand binding site yet have very different pharmacological properties. Analysis of the pharmacological properties of a series of chimeric 5-HT1D beta/5-HT1E receptors indicates that sequences in the sixth and seventh transmembrane domains are responsible for the differential affinity of 5-carboxamidotryptamine for these two receptors. More detailed analysis shows that two amino acid differences in the sixth transmembrane domain (Ile333 and Ser334 in the 5-HT1D beta receptor, corresponding to Lys310 and Glu311 in the 5-HT1E receptor) are largely responsible for the differential affinities of some, but not all, ligands for the 5-HT1D beta and 5-HT1E receptors. It is likely that these two amino acids subtly determine the overall three-dimensional structure of the receptor rather than interact directly with individual ligands.
authors.affiliation: Department of CNS Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Parker
authors.forename: D G
authors.initials: DG
authors.lastname: Izzarelli
authors.forename: L
authors.initials: L
authors.lastname: Lewis-Higgins
authors.forename: D
authors.initials: D
authors.lastname: Palmer
authors.forename: R A
authors.initials: RA
authors.lastname: Shapiro
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D017931:DNA Primers; D004873:Ergolines / Q000494:pharmacology; D018698:Glutamic Acid; D006801:Humans; D007532:Isoleucine; D007700:Kinetics; D008024:Ligands; D008239:Lysine; D008961:Models, Structural; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017433:Protein Structure, Secondary; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012694:Serine; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection
chemical_list: D017931:DNA Primers; D004873:Ergolines; D008024:Ligands; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D011993:Recombinant Fusion Proteins; C076396:serotonin 1E receptor; D007532:Isoleucine; D012701:Serotonin; D018698:Glutamic Acid; D012694:Serine; C047087:5-carboxamidotryptamine; D008239:Lysine; C061884:lysergol