Chemokine-Directed Trafficking of Receptor Stimulus to Different G Proteins: Selective Inducible and Constitutive Signaling by Human Herpesvirus 6-Encoded Chemokine Receptor U51

Fitzsimons, Carlos P.; Gompels, Ursula A.; Verzijl, Dennis; Vischer, Henry F.; Mattick, C; Leurs, Rob; Smit, Martine J.

doi:10.1124/mol.105.015222

Cited by 32 publications

(35 citation statements)

References 39 publications

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“…To account for response-dependent, agonist intrinsic efficacy, Kenakin (1995Kenakin ( , 2003 developed the concept of agonist-directed trafficking of receptor stimulus (also known as "functional selectivity"), which states that agonists promote/stabilize unique agonist-specific receptor conformational states that can differentially activate effectors. Agonist functional selectivity has been supported by evidence obtained with neurotensin NTS1 receptors (Skrzydelski et al, 2003), dopamine receptors (Meller et al, 1992;Gay et al, 2004), opioid receptors (Piñ eyro and Archer-Lahlou, 2007), cannabinoid receptors (Shoemaker et al, 2005), chemokine receptors (Fitzsimons et al, 2006), and 5-HT 2A and 5-HT 2C receptors (Berg et al, 1998;Kurrasch-Orbaugh et al, 2003), among others (Urban et al, 2007).…”

mentioning

confidence: 75%

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)_2A and 5-HT_2C Receptors

Moya

Berg

Gutiérrez-Hernández

et al. 2007

J Pharmacol Exp Ther

104

117

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2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT) 2A/2C agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A 2 (PLA 2 )] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA 2 and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT 2A or 5-HT 2C receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT 2C receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT 2A receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT 2C receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT 2C receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA 2 -specific at the 5-HT 2A receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT 2A receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.

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confidence: 75%

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)_2A and 5-HT_2C Receptors

Moya

Berg

Gutiérrez-Hernández

et al. 2007

J Pharmacol Exp Ther

104

117

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“…This conserved, early expressed chemokine receptor, is required for efficient replication, and has sensitive signalling mechanisms, both inducible and constitutive, with immune regulatory function (Catusse et al, 2008;Fitzsimons et al, 2006;Milne et al, 2000;Zhen et al, 2005). This was combined with analyses of the divergent U46, encoding glycoprotein gN, a component in complex with gM, also essential for infection (Kawabata et al, 2012) and previously used to genotype the predominant HHV-6A virus infecting children in Zambia (Bates et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…While the U51A chemokine receptor has a complementary function, by affecting the key remaining beta-chemokine receptors. This gives U51 a unique specificity distinct from cellular receptors, having overlapping reactivities similar to CCR2, CCR3, XCR1 and CCR7, and combining both constitutive as well as inducible immunoregulatory signalling activities (Catusse et al, 2008;Fitzsimons et al, 2006;Milne et al, 2000). Unlike human chemokines, the U83A chemokine does not interact with DARC or D6 regulatory chemokine receptors.…”

Section: Uk-hivaids-u46-aj O Uganda-hivaids-u46-u1102mentioning

confidence: 99%

“…Both viruses encode potent immunomodulators. These include chemokines plus their receptors, which could dysregulate the inflammatory response, and these have different specificities (Catusse et al, 2008(Catusse et al, , 2009Dewin et al, 2006;Fitzsimons et al, 2006;Lüttichau et al, 2003). Studies in countries where HHV-6B is prevalent show that complications include childhood febrile status epilepticus, linked to hippocampus involvement and a risk factor for temporal lobe epilepsy development (Epstein et al, 2012), as well as cognitive dysfunction or fatal encephalitis in haematopoietic stem cell transplantation patients (Zerr, 2006;Zerr et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators

Tweedy

Spyrou

Hubáček

et al. 2015

Journal of General Virology

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Human herpesvirus-6A (HHV-6A) is rarer than HHV-6B in many infant populations. However, they are similarly prevalent as germline, chromosomally integrated genomes (ciHHV-6A/B). This integrated form affects 0.1-1 % of the human population, where potentially virus gene expression could be in every cell, although virus relationships and health effects are not clear. In a Czech/ German patient cohort ciHHV-6A was more common and diverse than ciHHV-6B. Quantitative PCR, nucleotide sequencing and telomeric integration site amplification characterized ciHHV-6 in 44 German myocarditis/cardiomyopathy and Czech malignancy/inflammatory disease (MI) patients plus donors. Comparisons were made to sequences from global virus reference strains, and blood DNA from childhood-infections from Zambia (HHV-6A mainly) and Japan (HHV-6B). The MI cohort were 86 % (18/21) ciHHV-6A, the cardiac cohort 65 % (13/20) ciHHV-6B, suggesting different disease links. Reactivation was supported by findings of 1) recombination between ciHHV-6A and HHV-6B genes in 20 % (4/21) of the MI cohort; 2) expression in a patient subset, of early/late transcripts from the inflammatory mediator genes chemokine receptor U51 and chemokine U83, both identical to ciHHV-6A DNA sequences; and 3) superinfection shown by deep sequencing identifying minor virus-variants only in ciHHV-6A, which expressed transcripts, indicating virus infection reactivates latent ciHHV-6A. Half the MI cohort had more than two copies per cell, median 5.2, indicative of reactivation. Remarkably, the integrated genomes encoded the secreted-active form of virus chemokines, rare in virus from childhoodinfections. This shows integrated virus genomes can contribute new human genes with links to inflammatory pathology and supports ciHHV-6A reactivation as a source for emergent infection.

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“…1). Constitutive signaling has so far been measured only for the HHV-6-encoded U51 gene (Fitzsimons et al, 2006). …”

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confidence: 99%

Herpesvirus-Encoded G Protein-Coupled Receptors as Modulators of Cellular Function

Maussang¹,

Vischer²,

Leurs³

et al. 2009

Molecular Pharmacology

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Human herpesviruses (HHVs) are widespread pathogens involved in proliferative diseases, inflammatory conditions, and cardiovascular diseases. During evolution, homologs of human chemokine receptors were integrated into the HHV genomes. In addition to binding endogenous chemokines, these viral G protein-coupled receptors (vGPCRs) have acquired the ability to signal in a constitutive manner. Ligand-induced and ligandindependent and autocrine and paracrine signaling properties of vGPCRs modify the functions of the expressing cells and lead to transformation and escape from immune surveillance. Furthermore, cross-talk or heterodimerization with endogenous chemokine receptors represent other ways for vGPCRs to modify intracellular signaling and cellular functions. As such, these viral receptors seem to play a prominent role during viral pathogenesis and life cycle and thus represent innovative antiviral therapies.G protein-coupled receptors (GPCRs) are essential mediators of cellular communication. Their cell surface expression allows easy access and activation by their extracellular ligands to initiate intracellular signaling cascades. The physiological role of GPCR activation ranges from gene transcription to cellular migration and proliferation. Besides being activated by their cognitive ligands, GPCRs can signal independently from ligand activation. This so-called constitutive activity is the molecular basis of various pathologies (Smit et al., 2007). It is noteworthy that, during evolution, human herpesviruses (HHV) of the ␤ and ␥ families hijacked human GPCR while coexisting with their host (Brunovskis and Kung, 1995). These viral GPCRs (vGPCRs) show considerable homology to chemokine receptors, which are essential in the development of the hematopoietic system and regulation of cellular homeostasis (Mackay, 2001). In addition, chemokine receptors play a prominent role in cancer development (e.g., by inducing cellular proliferation or by modifying cellular migration patterns), resulting in cancer metastasis (Balkwill, 2004). Although human chemokine receptors require ligand activation to exert a physiological function, most of the vGPCRs show high levels of constitutive activity (Vischer et al., 2006b). As for human GPCRs, the constitutive modulation of signaling pathways by vGPCRs may play a role in the development of HHV-related diseases. As such, these vGPCRs may serve as therapeutic targets for the intervention of viral pathogenesis. ␥-Herpesvirus-Encoded G Protein-Coupled ReceptorsThe Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) and the Epstein-Barr virus (EBV or HHV-4) are lymphotropic viruses that are involved in proliferative dis- Article, publication date, and citation information can be found at

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Chemokine-Directed Trafficking of Receptor Stimulus to Different G Proteins: Selective Inducible and Constitutive Signaling by Human Herpesvirus 6-Encoded Chemokine Receptor U51

Cited by 32 publications

References 39 publications

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)_2A and 5-HT_2C Receptors

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)_2A and 5-HT_2C Receptors

Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators

Herpesvirus-Encoded G Protein-Coupled Receptors as Modulators of Cellular Function

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Chemokine-Directed Trafficking of Receptor Stimulus to Different G Proteins: Selective Inducible and Constitutive Signaling by Human Herpesvirus 6-Encoded Chemokine Receptor U51

Cited by 32 publications

References 39 publications

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)2A and 5-HT2C Receptors

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)2A and 5-HT2C Receptors

Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators

Herpesvirus-Encoded G Protein-Coupled Receptors as Modulators of Cellular Function

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Product

Resources

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Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)_2A and 5-HT_2C Receptors

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)_2A and 5-HT_2C Receptors