G Protein–Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives

Ferré, Sergi; Casadó, Vicent; Devi, Lakshmi A.; Filizola, Marta; Jockers, Ralf; Lohse, Martin J.; Milligan, Graeme; Pin, Jean‐Philippe; Guitart, Xavier

doi:10.1124/pr.113.008052

Cited by 502 publications

(518 citation statements)

References 158 publications

(247 reference statements)

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“…Receptor crosstalk can be attributed to a variety of molecular mechanisms, including receptor hetero-oligomerization (14)(15)(16)(17)(18)(19)(20)(21)(22)(23). The formation of homoand/or hetero-oligomeric complexes among GPCRs is thought to be important for many aspects of GPCR function (22)(23)(24).…”

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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

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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

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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

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“…Development of allosteric ligands extends the repertoire of GPCR regulators (Smith 2010). GPCRs were originally considered to be monomeric, but increasing evidence indicates that they can form dimers and oligomers as well (Ferre et al, 2014 Piscitelli et al, 2015), has been described as a "crystallization boom" (Costanzi 2014), with rapid growth emerging due to recent technological advances in both crystallization and structure detection. The availability of growing numbers of experimentally-determined GPCR structures, as well as improved homology-modeling of unknown target proteins based on a wider field of experimentally determined GPCR template structures, allows visual representation of GPCRs to be built upon the basis of known or modeled three-dimensional structures.…”

Section: This Image Was Made With Visual Molecular Dynamics (Vmd) Vmmentioning

confidence: 99%

Section: This Image Was Made With Visual Molecular Dynamics (Vmd) Vmmentioning

confidence: 99%

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The Science Behind G Protein-Coupled Receptors (GPCRs) and Their Accurate Visual Representation in Scientific Research

Sojka¹,

Brennan²,

Maizels³

et al. 2017

JBC

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IntroductionG Protein-Coupled Receptors (GPCRs) are transmembrane (TM) proteins that span the cell membrane seven times, and contain intracellular and extracellular domains comprised of connecting loops as well as terminal extension sequences. GPCRs bind ligands within their transmembrane and/or extracellular domains. Ligand binding elicits conformational changes that initiate downstream intracellular signaling events through arrestins and G proteins ( Figure 1; Katritch et al., 2013). GPCRs play central roles in many physiological processes from sensory to neurological, cardiovascular, endocrine, and reproductive functions. GPCRs represent one of the largest gene families in the human genome, encoding approximately 800 unique proteins (Fredriksson et al., 2003). GPCRs' unique structure and cell surface location make them ideal targets for various drug therapies, assuring interest from the pharmaceutical and clinical medicine communities (Vischer et al., 2011). It is estimated that roughly 40% of the pharmaceuticals currently marketed, target GPCRs (Vischer et al., 2011). BI-167107, bovine Gs;Rasmussen et al., 2011) Urbana-Champaign (Humphreys et al., 1996). This image was made with Visual Molecular Dynamics (VMD). VMD is developed with NIH support by the Theoretical and Computational Biophysics group at the Beckman Institute, University of Illinois atThe elucidation of x-ray crystallographic structures of GPCRs has been monumental to the research in understanding the function and conformational flexibility of GPCRs (Costanzi 2014;Venkatakrishnan et al., 2014). Understanding how ligand binding alters the structure and function of GPCRs to mediate signaling has undergone an expansion in recent years (Katritch et al., 2013). Concepts such as ligands acting as functionally selective biased agonists to elicit a specific subset of signaling responses are now at the forefront of GPCR research (Andresen 2011). Development of allosteric ligands extends the repertoire of GPCR regulators (Smith 2010). GPCRs were originally considered to be monomeric, but increasing evidence indicates that they can form dimers and oligomers as well (Ferre et al., 2014 Piscitelli et al., 2015), has been described as a "crystallization boom" (Costanzi 2014), with rapid growth emerging due to recent technological advances in both crystallization and structure detection. The availability of growing numbers of experimentally-determined GPCR structures, as well as improved homology-modeling of unknown target proteins based on a wider field of experimentally determined GPCR template structures, allows visual representation of GPCRs to be built upon the basis of known or modeled three-dimensional structures. Nevertheless, several challenges to accurate communication of GPCR structure remain.The goal of this paper is to provide strategies to address common visual representation challenges for GPCRs, and to identify errors that may arise from an incomplete understanding of GPCR structure. GPCRs comprise a subclass of the alpha-helical membrane p...

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“…In particular, he proposed that the DA i receptor could be linked to a serotonin receptor, while the DA e receptor may be linked to an α-adrenoceptor. Although he did not pursue this hypothesis in great detail, the existence of receptor dimers or oligomers is now well established, both within one neurotransmitter, such as dopamine (Perreault et al 2011), as well as between different neurotransmitter systems (Ferre et al 2014;Fuxe et al 2005;Wang et al 2012).…”

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confidence: 99%

Alexander Rudolf Cools (1942–2013)

et al. 2014

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G Protein–Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives

Cited by 502 publications

References 158 publications

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

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

The Science Behind G Protein-Coupled Receptors (GPCRs) and Their Accurate Visual Representation in Scientific Research

Alexander Rudolf Cools (1942–2013)

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G Protein–Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives

Cited by 502 publications

References 158 publications

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

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

The Science Behind G Protein-Coupled Receptors (GPCRs) and Their Accurate Visual Representation in Scientific Research

Alexander Rudolf Cools (1942–2013)

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

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