Two Amino Acid Differences in the Sixth Transmembrane Domain Are Partially Responsible for the Pharmacological Differences Between the 5‐HT1Dβ and 5‐HT1E 5‐Hydroxytryptamine Receptors

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Abstract
5-Hydroxytryptamine elicits its physiological effects by interacting with a diverse group of receptors. Two of these receptors, the 5-HT1Dβ and the 5-HT1E receptors, are ∼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-HT1Dβ/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-HT1Dβ 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-HT1Dβ 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.

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