Receptor Conformation and Constitutive Activity in CCR5 Chemokine Receptor Function and HIV Infection

Flanagan, Colleen A.

doi:10.1016/b978-0-12-417197-8.00008-0

Cited by 25 publications

(20 citation statements)

References 235 publications

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“…Another possibility is that dopamine-mediated changes in CCR5 could increase viral entry. CCR5 is present on the cell surface in multiple conformational states [118] , and studies show different conformations of this receptor increase the binding affinity or accessibility of CCR5 to HIV, changing the efficiency of entry or fusion [119] – [121] . In macrophage-tropic CNS viruses, changes in the interaction of gp120 with the 1 st and 2 nd extracellular loop regions and the N-Terminus increased the efficiency of HIV infection [120] .…”

Section: Discussionmentioning

confidence: 99%

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

et al. 2014

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Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.

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Section: Discussionmentioning

confidence: 99%

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

et al. 2014

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“…In addition to inducing Ca 2+ flux, activation of G proteins through CCR5 also leads to inhibition of cyclic adenosine monophosphate (cAMP) generation, an effect of G i/o protein activation. However, it is less clear whether Ca 2+ flux is a result of G q protein activation or release of G subunits after G i/o protein activation in the context of CCR5 (13). 5P14, which does not trigger CCR5-mediated Ca 2+ flux, does inhibit cAMP production (14).…”

Section: Introductionmentioning

confidence: 99%

G protein subtype–specific signaling bias in a series of CCR5 chemokine analogs

et al. 2018

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Chemokines and some chemical analogs of chemokines prevent cellular HIV-1 entry when bound to the HIV-1 coreceptors C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4), which are G protein–coupled receptors (GPCRs). The ideal HIV-1 entry blocker targeting the coreceptors would display ligand bias and avoid activating G protein–mediated pathways that lead to inflammation. We compared CCR5-dependent activation of second messenger pathways in a single cell line. We studied two endogenous chemokines [RANTES (also known as CCL5) and MIP-1α (also known as CCL3)] and four chemokine analogs of RANTES (5P12-, 5P14-, 6P4-, and PSC-RANTES). We found that CCR5 signaled through both Gi/o and Gq/11. IP1 accumulation and Ca2+ flux arose from Gq/11 activation, rather than from Gβγ subunit release after Gi/o activation as had been previously proposed. The 6P4- and PSC-RANTES analogs were superagonists for Gq/11 activation, whereas the 5P12- and 5P14-RANTES analogs displayed a signaling bias for Gi/o. These results demonstrate that RANTES analogs elicit G protein subtype–specific signaling bias and can cause CCR5 to couple preferentially to Gq/11 rather than to Gi/o signaling pathways. We propose that G protein subtype–specific signaling bias may be a general feature of GPCRs that can couple to more than one G protein family.

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“…Chemokine receptors and their ligand axis play pivotal roles in leukocyte migration, differentiation, adhesion, and activation [ 32 , 33 ]. Many chemokine receptors have been implicated in the pathogenesis of autoimmune connective tissue diseases such as SLE, rheumatoid arthritis (RA), and systemic sclerosis (SS) [ 19 – 21 , 32 , 34 – 37 ]. However, previous studies have demonstrated the indispensable role of chemokine receptors in autoimmune diseases, highlighting the role of Gi protein-coupled chemokine receptors (rather than Gq-coupled receptors) in directing the migration of immune cells, which mostly signal through the canonical AC pathway [ 19 , 36 ].…”

Section: The Diversity Of Gq-coupled Receptors In Autoimmunitymentioning

confidence: 99%

“…Autoimmunity-associated chemokine receptors mainly include the CC family (CCR5 and CCR7) and the CXC family (CXCR3, CXCR4, CXCR5, and CXCR7) [ 19 , 20 , 34 , 36 – 41 ]. To date, most chemokine receptors, such as CXCR4 and CXCR5 on T cells and B cells, have been shown to be induced by Gi in the classic pathway, while CCR7 and CXCR4 have been shown to be dependent on Gq pathways only on dendritic cells (DCs) [ 38 ].…”

Section: The Diversity Of Gq-coupled Receptors In Autoimmunitymentioning

confidence: 99%

Gq-Coupled Receptors in Autoimmunity

Zhang

Shi

2016

Journal of Immunology Research

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Heterotrimeric G proteins can be divided into Gi, Gs, Gq/11, and G12/13 subfamilies according to their α subunits. The main function of G proteins is transducing signals from G protein coupled receptors (GPCRs), a family of seven transmembrane receptors. In recent years, studies have demonstrated that GPCRs interact with Gq, a member of the Gq/11 subfamily of G proteins. This interaction facilitates the vital role of this family of proteins in immune regulation and autoimmunity, particularly for Gαq, which is considered the functional α subunit of Gq protein. Therefore, understanding the mechanisms through which Gq-coupled receptors control autoreactive lymphocytes is critical and may provide insights into the treatment of autoimmune disorders. In this review, we summarize recent advances in studies of the role of Gq-coupled receptors in autoimmunity, with a focus on their pathologic role and downstream signaling.

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Receptor Conformation and Constitutive Activity in CCR5 Chemokine Receptor Function and HIV Infection

Cited by 25 publications

References 235 publications

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

G protein subtype–specific signaling bias in a series of CCR5 chemokine analogs

Gq-Coupled Receptors in Autoimmunity

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