Interaction of Substance P with the Second and Seventh Transmembrane Domains of the Neurokinin-1 Receptor

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Abstract
The neurokinin-1 receptor is a member of the G-protein-coupled receptor family and has the highest affinity for the endogenous peptide transmitter substance P. Previous studies have indicated that several residues in the first and second extracellular segments, and at least part of the transmembrane domain, of the human neurokinin-1 receptor are involved in substance P binding to the receptor. To further map the peptide binding site, single-residue substitutions in the transmembrane domains were analyzed. Asn-85, Asn-89, Tyr-92, and Asn-96 in the second transmembrane domain and Tyr-287 in the seventh transmembrane domain are required for the high-affinity binding of peptides, with Asn-85 possibly interacting with the C-terminus of substance P. In addition, Glu-78 in the second transmembrane domain and Tyr-205 in the fifth transmembrane domain appear to be involved in the receptor activation process. Some of the key residues for peptide binding are likely to be near those residues that are required for the binding of competitive antagonists (such as His-197, His-265, and Tyr-287). These data suggest that a volume exclusion effect can explain the competitive antagonism of substance P binding by non-peptide antagonists. Furthermore, the key residues identified thus far are required for the high-affinity binding of all three neurokinin peptides, consistent with a hypothesis that the conformational compatibility between the receptor and the peptide agonist may be a major determinant of peptide recognition.