Blocking HIV-1 infection via CCR5 and CXCR4 receptors by acting in trans on the CCR2 chemokine receptor

Rodrı́guez-Frade, José Miguel; Real, Gustavo del; Serrano, Antonio; Hernanz‐Falcón, Patricia; Soriano, Silvia F.; Vila-Coro, Antonio J.; Ana, Ana Martı́n de; Lucas, Pilar; Priéto, Ignacio; Martı́nez-A, Carlos; Mellado, Mario

doi:10.1038/sj.emboj.7600020

Cited by 64 publications

(51 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The V64I CCR2 polymorphism has also been shown to enhance heterodimerization between CCR2/ CCR5 and CCR2/CXCR4 (Mellado et al, 1999). Considered together with data revealing that anti-CCR2 antibodies that enhance CCR2/CCR5 and CCR2/ CXCR4 heterodimerization also lead to markedly decreased HIV infectivity (Rodriguez-Frade et al, 2004), these findings suggest that heterodimerization of chemokine receptors is a key determinant in the ability of HIV to use these receptors to gain entry into cells. Heterodimerization of CCR2 and CCR5 has also been shown to result in synergistic signaling between the two receptors (Mellado et al, 2001), revealing that the interaction of these receptors has physiological rele- Marshall, 2001;George et al, 2002;Kroeger et al, 2003;Milligan, 2004;Terrillon and Bouvier, 2004b George et al, 2000;Gomes et al, 2000Gomes et al, , 2004 n.d., not determined.…”

Section: Clinical Significance Of Gpcr Heterodimerizationmentioning

confidence: 91%

Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance

2005

View full text Add to dashboard Cite

Section: Clinical Significance Of Gpcr Heterodimerizationmentioning

confidence: 91%

Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance

2005

View full text Add to dashboard Cite

“…CXCR4 has been shown to associate with multiple chemokine receptors in various expression systems (3,(25)(26)(27)(28). ARs are also known to be able to form heteromeric receptor complexes (29)(30)(31)(32)(33)(34)(35), and recent evidence suggests that AR may also be able to form heteromeric complexes with chemokine receptors (36)(37)(38).…”

mentioning

confidence: 99%

Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function

Abhishek

Vana

Chavan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

118

View full text Add to dashboard Cite

Recent evidence suggests that chemokine (C-X-C motif) receptor 4 (CXCR4) contributes to the regulation of blood pressure through interactions with α 1 -adrenergic receptors (ARs) in vascular smooth muscle. The underlying molecular mechanisms, however, are unknown. Using proximity ligation assays to visualize single-molecule interactions, we detected that α 1A/B -ARs associate with CXCR4 on the cell surface of rat and human vascular smooth muscle cells (VSMC). Furthermore, α 1A/B -AR could be coimmunoprecipitated with CXCR4 in a HeLa expression system and in human VSMC. A peptide derived from the second transmembrane helix of CXCR4 induced chemical shift changes in the NMR spectrum of CXCR4 in membranes, disturbed the association between α 1A/B -AR and CXCR4, and inhibited Ca 2+ mobilization, myosin light chain (MLC) 2 phosphorylation, and contraction of VSMC upon α 1 -AR activation. CXCR4 silencing reduced α 1A/B -AR:CXCR4 heteromeric complexes in VSMC and abolished phenylephrine-induced Ca 2+ fluxes and MLC2 phosphorylation. Treatment of rats with CXCR4 agonists (CXCL12, ubiquitin) reduced the EC 50 of the phenylephrineinduced blood pressure response three-to fourfold. These observations suggest that disruption of the quaternary structure of α 1A/B -AR:CXCR4 heteromeric complexes by targeting transmembrane helix 2 of CXCR4 and depletion of the heteromeric receptor complexes by CXCR4 knockdown inhibit α 1 -AR-mediated function in VSMC and that activation of CXCR4 enhances the potency of α 1 -AR agonists. Our findings extend the current understanding of the molecular mechanisms regulating α 1 -AR and provide an example of the importance of G protein-coupled receptor (GPCR) heteromerization for GPCR function. Compounds targeting the α 1A/B -AR:CXCR4 interaction could provide an alternative pharmacological approach to modulate blood pressure.CXCL12 | ubiquitin | AMD3100 | phenylephrine | blood pressure

show abstract

“…Recent evidence shows that chemokines interfere with MOR and KOR antinociceptive activity [49,50]. CXCR4 forms homo- [22,51] and heterodimers [38,52] at the cell surface. Our data are compatible with a model in which the receptor conformation stabilized depends on several factors including (i) receptor levels at the cell surface, (ii) ligand levels in the cell microenvironment, and (iii) the presence of other factors that alter receptor or ligand expression and function.…”

mentioning

confidence: 99%

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

et al. 2008

Self Cite

View full text Add to dashboard Cite

The CXCR4 chemokine receptor and the delta opioid receptor (DOR) are pertussis toxinsensitive G protein-coupled receptors (GPCR). Both are widely distributed in brain tissues and immune cells, and have key roles in inflammation processes and in pain sensation on proximal nerve endings. We show that in immune cells expressing CXCR4 and DOR, simultaneous addition of their ligands CXCL12 and [D-Pen2, DPen5]enkephalin does not trigger receptor function. This treatment does not affect ligand binding or receptor expression, nor does it promote heterologous desensitization. Our data indicate that CXCR4 and DOR form heterodimeric complexes that are dynamically regulated by the ligands. This is compatible with a model in which GPCR oligomerization leads to suppression of signaling, promoting a dominant negative effect. Knockdown of CXCR4 and DOR signaling by heterodimerization might have repercussions on physiological and pathological processes such as inflammation, pain sensation and HIV-1 infection.Supporting Information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2008/37630_s.pdf See accompanying article: http://dx.doi.org/10.1002/eji200738101 IntroductionThe G protein-coupled receptors (GPCR) represent the largest, most diverse family of transmembrane receptors expressed in the body. They act through G proteins to regulate intracellular processes including cell adhesion, migration and proliferation [1]. Studies show that the GPCR can function as oligomers [2,3]. Perhaps their most striking feature is that GPCR form not only functional homo-oligomers, but can also associate with other GPCR to form hetero-oligomers. Homo-and hetero-oligomers differ in their pharmacological pro- files, ligand binding affinity, and/or internalization pathways [4][5][6]. GPCR hetero-oligomerization would thus enable generation of new types of signaling units. Opioid and chemokine receptors are members of the Ga i protein-linked GPCR. These receptors and their ligands are expressed in neurons and glial cells, and in immune system cells such as lymphocytes, monocytes and neutrophils [7]. They share the same microenvironment in many physiological situations and are essential for inflammation processes. 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]. 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 [1...

show abstract

Blocking HIV-1 infection via CCR5 and CXCR4 receptors by acting in trans on the CCR2 chemokine receptor

Cited by 64 publications

References 51 publications

Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance

Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance

Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function

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

Contact Info

Product

Resources

About

Blocking HIV-1 infection via CCR5 and CXCR4 receptors by acting in trans on the CCR2 chemokine receptor

Cited by 64 publications

References 51 publications

Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance

Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

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

Contact Info

Product

Resources

About

Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function