NDLI: Constitutive Activation of the δ Opioid Receptor by Mutations in Transmembrane Domains III and VII

Content Provider	Journal of Biological Chemistry (JBC)
Author	Befort, Katia Zilliox, Christelle Filliol, Dominique Yue, ShiYi Kieffer, Brigitte L.
Abstract	We have investigated whether transmembrane amino acid residues Asp128 (domain III), Tyr129(domain II), and Tyr308 (domain VII) in the mouse δ opioid receptor play a role in receptor activation. To do so, we have used a [35S]GTPγS (where GTPγS is guanosine 5′-3-O-(thio)triphosphate) binding assay to quantify the activation of recombinant receptors transiently expressed in COS cells and compared functional responses of D128N, D128A, Y129F, Y129A, and Y308F point-mutated receptors to that of the wild-type receptor. In the absence of ligand, [35S]GTPγS binding was increased for every mutant receptor under study (1.6–2.6-fold), suggesting that all mutations are able to enhance constitutive activity at the receptor. In support of this finding, the inverse agonistN,N-diallyl-Tyr-Aib-Aib-Phe-Leu (where Aib represents α-aminobutyric acid) efficiently reduced basal [35S]GTPγS binding in the mutated receptor preparations. The potent agonist BW373U86 stimulated [35S]GTPγS binding above basal levels with similar (D128N, Y129F, and Y129A) or markedly increased (Y308F) efficacy compared with wild-type receptor. BW373U86 potency was maintained or increased. In conclusion, our results demonstrate that the mutations under study increase functional activity of the receptor. Three-dimensional modeling suggests that Asp128 (III) and Tyr308 (VII) interact with each other and that Tyr129 (III) undergoes H bonding with His278(VI). Thus, Asp128, Tyr129, and Tyr308 may be involved in a network of interhelical bonds, which contributes to maintain the δ receptor under an inactive conformation. We suggest that the mutations weaken helix-helix interactions and generate a receptor state that favors the active conformation and/or interacts with heterotrimeric G proteins more effectively.
Related Links	http://www.jbc.org/content/274/26/18574.abstract
Ending Page	18581
Starting Page	18574
Page Count	8
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	26
Volume Number	274
DOI	10.1074/jbc.274.26.18574
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1999-06-25
Access Restriction	Open
Subject Keyword	Transmembrane domain (Tm) Constitutively active mutant (CAM) [D-Ala2, D-Leu5]enkephalin (DADLE) Cloned mouse δ-opioid receptor (mDOR) G protein-coupled receptors (GPRs) N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (where Aib represents α-aminobutyric acid) (ICI174864) Wild type (WT) Guanosine 5′-3-O-(thio)triphosphate (GTPγS) PROTEIN CHEMISTRY AND STRUCTURE (±)-4-[(a-R)-a-[(2S,5R*)-4-allyl-2,5-di-methyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide (BW-373U86) ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide) (SNC80)
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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