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Residue 78 in the second transmembrane domain of the neurokinin-1 receptor is important in coupling high affinity agonist binding to multiple second messenger responses

RM Brodbeck, BS Sachais and JE Krause

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

The neurokinin-1 tachykinin receptor is a member of the G protein- coupled receptor superfamily. An unusual feature of the neurokinin-1 receptor is the presence of glutamic acid (residue 78) in the second putative transmembrane domain, at the location of a highly conserved aspartate residue in the G protein-coupled receptor superfamily. The rat neurokinin-1 receptor cDNA was mutated to lysine, aspartate, and glutamine at this site and functionally expressed in Chinese hamster ovary cells, and clonal cell lines were isolated and characterized. Radioligand binding demonstrated that the Asp78 and Lys78 receptors have substance P binding affinities indistinguishable from those of the wild-type receptor and are expressed at roughly the same number of receptors per cell. The Gln78 receptor variant, on the other hand, exhibited no detectable agonist binding. Although wild-type and Asp78 receptors have essentially the same ability to stimulate inositol phospholipid turnover, cAMP production, and arachidonic acid release, the Lys78 variant is markedly attenuated in its ability to activate any of these pathways. These data indicate that residue 78 plays a role in the coupling of the rat neurokinin-1 receptor to cellular effectors. In addition, both Asp78 and Lys78 receptors show a greater percentage of high affinity binding that is resistant to guanosine-5'-O-(3- thio)triphosphate than does the wild-type receptor, indicating a potential difference in G protein coupling between wild-type and mutated receptors.

Volume 47, Issue 5, pp. 1065-1071, 05/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics




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