Cell surface targeting of mu-delta opioid receptor heterodimers by RTP4.
Mu opioid receptors are G protein-coupled receptors that mediate the pain-relieving effects of clinically used analgesics, such as morphine. Accumulating evidence shows that mu-delta opioid heterodimers have a pharmacologic profile distinct from those of the mu or delta homodimers. Because the heterodimers exhibit distinct signaling properties, the protein and mechanism regulating their levels have significant effects on morphine-mediated physiology. We report the characterization of RTP4, a Golgi chaperone, as a regulator of the levels of heterodimers at the cell surface. We show that the association with RTP4 protects mu-delta receptors from ubiquitination and degradation. This leads to increases in surface heterodimer levels, thereby affecting signaling. Thus, the oligomeric organization of opioid receptors is controlled by RTP4, and this governs their membrane targeting and functional activity. This work is the first report of the identification of a chaperone involved in the regulation of the biogenesis of a family A GPCR heterodimer. The identification of such factors as RTP4 controlling dimerization will provide insight into the regulation of heterodimers in vivo. This has implications in the modulation of pharmacology of their endogenous ligands, and in the development of drugs with specific therapeutic effects.
Décaillot
Fabien M
FM
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Rozenfeld
Raphael
R
Gupta
Achla
A
Devi
Lakshmi A
LA
D000818:Animals; D002460:Cell Line; D019281:Dimerization; D006801:Humans; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D018832:Molecular Chaperones / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D054875:Ubiquitination
D026901:Membrane Transport Proteins; D018832:Molecular Chaperones; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C533090:Rtp4 protein, mouse