Receptor Heterodimerization with Opioid Receptors

Chemokine Receptor Heterodimerization with Opioid Receptors 

Chemokine Receptor Heterodimers Innovative Drug Taigets  

is supported by a Veni grant from the The Netherlands Organization for Scientific Research (NWO). 

and Luster, A.D. (2008) Chemokines and their receptors drug targets in immunity and inflammation. Annucd Review of Pharmacolog/ and Toxicology, 48, 171-197. 

and Proudfoot, A.E. (2006) Chemokine blockers-therapeutics in the making Trends in Pharmacological Sciences, 27, 41 7. 

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Chemokine Receptor Heterodimerization with Opioid Receptors... 

The existence of further alternative transcripts of MOP was postulated by the observation that in knockout mice with disrupted exon 1, heroin but not morphine was still analgesically active. Based on earlier observations that the antagonist naloxazone blocked morphine-induced antinociception but not morphine-induced respiratory depression, a subdivision of the MOP in pi and p2 was proposed. However, no discrete mRNA for each of these MOP subtypes has been found. It is, however, possible that subtypes of MOPs result from heterodimerization with other opioid receptors or by interaction with other proteins. 

There has been an extensive search for additional opioid receptor genes with homology to p, 8, and k receptors which was, however, unsuccessfiil. It is likely, therefore, that the functional properties of the subdivision of p, 8, and k receptors as well as that of the e and X receptors results from alternate mRNA processing, posttranslational modification of the receptor, and/ or from the formation of homo- and heterodimeric receptor complexes. 

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. 

Application of the SCM method to the opioid receptor subtypes (187,188) supported the experimental evidence of subtype specificity in the process of heterodimerization of these receptors (96). Although likely heterodimerization interfaces of the 5-p and 5-k opioid receptor complexes were predicted using the SCM method, the application of this procedure to explore the putative interface between p and k opioid receptors resulted in a null set for residues that indicates the absence of a predicted dimerization interface. This result is in full agreement with previous experimental observations (96). 

Moreover, in a tolerance study using the mouse tail-flick test, p agonist 74 with a spacer produced tolerance but twin drugs 71a and 72 induced no significant tolerance. Taken together, these results suggest that the heterodimerization of p opioid and CCK2 receptors would not be relevant to blockade of tolerance. The twin... 

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