GPCRs opioid receptors

Cox BM et al (2005) Opioid receptors. NC-IUPHAR receptor data base (www.iuphar-db.org/GPCR)... 

Three endogenous opioids have been identified enkephalins, dynorphins and beta-endorphins. These opioid peptides selectively bind to the seven transmembrane GPCRs delta (8), kappa (k), and mu (p). Although dynorphin binds predominately to the k receptor, P-endorphines and enkephalins bind to p and 8 opioid receptors. It is important to note that the analgesia induced by opioids is mediated predominately throngh the p opioid receptor. In vitro studies have shown a decrease in the immnne function and proliferation following p-endorphin administration in rodents (Ray and Cohn 1999) and that the immunosuppressive effects by P-endorphins are steroid-independent (Berkenbosch et al. 1984 Nelson et al. 2000). 

The GPCR C-terminal region, with or without a coiled-coil motif, has been implicated in the heterodimerization process of GABAb(1)-GABAb(2) (78,80), as well as in the homodimerization of 5-opioid receptor (120). However, the possibility cannot be ruled out that the indirect evidence for the involvement of the C-terminal domain results from changes produced by the deletion of the C-terminal tail, that alters the conformation of the receptors and causes decreased interactions between transmembrane helices and oligomer disruption. 

In case of the P -adrenergic receptor, phosphorylation of serine and threonine residues in the carboxyl tail can be shown to be involved in desensitization and internalization (141,156). Other GPCRs—such as the p- and 5-opioid receptors... 

The 5 opioid receptor sequence comprises 372 amino acids with seven putative transmembrane domains. The 5 receptor belongs to the GPCR superfamily. The alignment of mouse, rat and human 5 opioid receptor sequences shows highly homologous sequences among these species (Knapp et al., 1994 Jin et al., 1999). 

The delta opioid receptor is a member of the large family of seven trans-membrane-spanning G protein-coupled receptors (GPCRs), as discussed extensively in Chapter 2. Delta opioid receptors modulate many intracellular effectors through their activation of GTP-binding proteins (G proteins), including adenylyl cyclase, K+ channels, Ca2+ channels, the MAP kinase cascade, phospholipase C, and intracellular Ca2+ release [1] (see Chap. 5). 

Agonist occupancy of GPCRs, such as the delta opioid receptor, leads to physiological effects through interactions with heterotrimeric G proteins. Such G proteins consist of a Ga subunit and its Gpy dimeric partner. There are four major families of Ga proteins with different profiles of effector interaction 1) Gas, which activate adenylyl cyclase 2) Gai/o, so-called inhibitory G proteins named for their ability to inhibit adenylyl cyclase, but interact with many effectors 3) Gaq/11, which activate phospholipase C- 3 (PLC- 3) and 4) Gal2/13, which may regulate small GTP-binding proteins. Delta opioid receptors, like mu and kappa opioid receptors, couple to mem-... 

Got subunits of the Gi/o type of G proteins can be ADP-ribosylated in the presence of pertussis toxin at Cys351, four amino acids from the C-terminus. Petussis toxin sensitivity is the major method of identifying a role for Gai/o proteins in GPCR-mediated signaling. This treatment prevents receptor-mediated G-protein activation and thus exchange of GTP for GDP and so blocks signaling by Ga and G(3y. There are numerous examples of the use of this technique to identify coupling of the delta opioid receptor [e.g., 2,3,41,42,73,77]. One Ga protein in this class, Gaz, lacks the Cys residue that is the site for pertussis toxin action and so is insensitive to pertussis toxin treatment [see 17 for review]. 

There are four major classes of opioid receptors mu, kappa, delta, and NOP receptors (see http //www.iuphar-db.org/ GPCR/ChapterMenuForv ard chapterID = 1295). Pharmacological studies in many species and knockout studies in mice indicate that the mu opioid receptors (MOP receptors MOR OP receptors) are involved in most of the clinically important effects associated with opioid drugs (Matthes et al., 1996 ... 

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