2 AMINO-ACID DIFFERENCES IN THE 6TH TRANSMEMBRANE DOMAIN ARE PARTIALLY RESPONSIBLE FOR THE PHARMACOLOGICAL DIFFERENCES BETWEEN THE 5-HT1D-BETA AND 5-HT1E 5-HYDROXYTRYPTAMINE RECEPTORS

5-Hydroxytryptamine elicits its physiological effects by interacting w ith a diverse group of receptors. Two of these receptors, the 5-HT1D b eta and the 5-HT1E receptors, are similar to 60% identical in the tran smembrane domains that presumably form the ligand binding site yet hav e very different pharmacological properties. Analysis of the pharmacol ogical properties of a series of chimeric 5-HT1D beta/5-HT1E receptors indicates that sequences in the sixth and seventh transmembrane domai ns are responsible for the differential affinity of 5-carboxamido-tryp tamine for these two receptors. More detailed analysis shows that two amino acid differences in the sixth transmembrane domain (lle(333) and Ser(334) in the 5-HT1D beta receptor, corresponding to Lys(310) and G lu(311) in the 5HT(1D beta) receptor) are largely responsible for the differential affinities of some, but not all, ligands for the 5-HT1D b eta and 5-HT1E receptors. It is likely that these two amino acids subt ly determine the overall three-dimensional structure of the receptor r ather than interact directly with individual ligands.