Heterodimerization and cross-desensitization between the μ-opioid receptor and the chemokine CCR5 receptor

Ligand stabilization of CXCR4/δ‐opioid receptor heterodimers reveals a mechanism for immune response regulation

“…CXCL12-induced JK cell migration was inhibited by simultaneous DPDPE addition only when JK cells expressed equivalent CXCR4 and DOR levels. Concurring with studies showing heterodimer formation between CCR5 and the three opioid receptor subtypes [8,10], our FRET data corroborated formation of stable CXCR4/DOR complexes, even in the absence of ligands, and IP experiments demonstrated digitonin-resistant CXCR4/DOR heterodimers. Formation of these complexes depends on receptor expression levels, as CXCR4 homodimers were disrupted after DOR expression.…”

“…The opioid effect on chemokinemediated lymphocyte migration is better established; opioids incubated with leukocytes prevent cell movement toward chemokines [12]. These observations suggest interaction; in fact, cross-desensitization processes are described between the two receptor types [8,10].Here, we observed that the combination of DOR and CXCR4 ligands specifically abolished CXCR4-induced migration and adhesion of cell lines and of primary monocytes, and that the DOR antagonist naltrindole reversed this effect. These experiments also confirmed that DPDPE promotes potent MM-1 cell adhesion, which was greater than that promoted by CXCL12, and was blocked by simultaneous CXCL12 addition.…”

“…Chemokine receptors promote immune cell migration to and adhesion at the inflammation site, whereas opioid receptors reduce pain sensation on proximal nerve endings. Opioid receptors can also regulate the immune response, as they alter antibody responses, cell-mediated immunity, phagocytic activity, adhesion and chemotaxis [8][9][10][11]. Opioids also prevent leukocyte movement toward chemokine gradients [12], and cross-desensitization is described between opioid and chemokine receptors [8,10].…”

“…Opioids also prevent leukocyte movement toward chemokine gradients [12], and cross-desensitization is described between opioid and chemokine receptors [8,10]. The CCR5 chemokine receptor can form heterodimers with each of the three opioid receptor subtypes (l, d, and j) [8,10].CXCR4, the most widely expressed chemokine receptor [13], is crucial for correct lymphocyte trafficking [14], hematopoiesis, and development [15][16][17]. It is also a coreceptor for T-tropic HIV strains [18,19], and participates in tumor cell metastasis [20][21].…”

“…The results confirmed that DOR-CXCR4 complexes also form in primary cells in a ligand-independent manner. Many reports show that CXCR4 and DOR form homoand heterodimers [8,10,22,37,38]. To determine whether these conformations are fixed or in dynamic equilibrium, we cotransfected HEK293 cells with CXCR4-CFP, CXCR4-YFP and increasing amounts of DOR.…”