1,721,413 research outputs found
Chemokine receptor CCR5: insights into structure, function, and regulation
No full textCC chemokine receptor 5 (CCR5) is a seven-transmembrane, G protein-coupled receptor (GPCR) which regulates trafficking and effector functions of memory/effector T-lymphocytes, macrophages, and immature dendritic cells. It also serves as the main coreceptor for the entry of R5 strains of human immunodeficiency virus (HIV-1, HIV-2). Chemokine binding to CCR5 leads to cellular activation through pertussis toxin-sensitive heterotrimeric G proteins as well as G protein-independent signalling pathways, Like many other GPCR, CCR5 is regulated by agonist-dependent processes which involve G protein coupled receptor kinase (GRK)-dependent phosphorylation, P-arrestin-mediated desensitization and internalization. This review discusses recent advances in the elucidation of the structure and function of CCR5, as well as the complex mechanisms that regulate CCR5 signalling and cell surface expression. (C) 2004 Elsevier Inc. All rights reserved
Phosphorylation-state specific monoclonal antihodies reveal phosphorylation of distinct serine residues on chemokine receptor CCR5 by G protein-coupled receptor kinases (GRK) versus protein kinase C (PKC)
No full textPhosphorylation-state specific monoclonal antihodies reveal phosphorylation of distinct serine residues on chemokine receptor CCR5 by G protein-coupled receptor kinases (GRK) versus protein kinase C (PKC)
No full textG protein-coupled receptor kinases promote phosphorylation and beta-arrestin-mediated internalization of CCR5 homo- and hetero-oligomers
No full textExpression levels of the chemokine receptor, CC chemokine receptor 5 (CCR5), at the cell surface determine cell susceptibility to HIV entry and infection. Cellular activation by CCR5 itself, but also by unrelated receptors leads to cross-phosphorylation and cross-internalization of CCR5. This study addresses the underlying molecular mechanisms of homologous and heterologous CCR5 regulation. As shown by bioluminescence resonance energy transfer experiments, CCR5 formed constitutive homo- as well as heterooligomeric complexes together with C5aR but not with the unrelated AT(1a)R in living cells. Stimulation with CCL5 of RBL cells, which co-expressed CCR5 together with an N-terminally truncated CCR5-Delta NT mutant, resulted in both protein kinase C(PKC)- and G protein-coupled receptor (GPCR) kinase (GRK)-mediated cross-phosphorylation of the mutant unligated receptor, as determined by phosphosite-specific monoclonal antibody. Similarly, both PKC and GRK cross-phosphorylated CCR5 in a heterologous manner after C5a stimulation of RBL-CCR5/ C5aR cells, whereas AT(1a)R stimulation resulted only in classical PKC-mediated CCR5 phosphorylation. Co-expression of CCR5-Delta NT together with a phosphorylation-deficient CCR5 mutant that neither binds beta-arrestin nor undergoes internalization partially restored the CCL5-induced association of beta-arrestin with the homo- oligomeric receptor complex and augmented cellular uptake of I-125-CCL5. Co-expression of C5aR, but not of AT1aR, promoted CCR5 co-internalization upon agonist stimulation by a mechanism independent of CCR5 phosphorylation. Co-internalization of phosphorylated CCR5 was also observed in C5a-stimulated macrophages. Finally, co-expression of a constitutively internalized C5aR-US28(CT) mutant led to intracellular accumulation of CCR5 in the absence of ligand stimulation. These results show that GRKs and beta-arrestin are involved in heterologous receptor regulation by cross-phosphorylating and co-internalizing unligated receptors within homo- or hetero-oligomeric protein complexes
Targetting CCL25/CCR9: A succesful therapeutic strategy during early chronic murine ileitis
No full textKinetic analysis of PKC- and GRK-mediated phosphorylation of chemokine receptor CCR5 by phosphosite-specific antibodies
No full textChronic morphine induces the concomitant phosphorylation and altered association of multiple signaling proteins: A novel mechanism for modulating cell signaling
No full textTraditional mechanisms thought to underlie opioid tolerance include receptor phosphorylation/down-regulation, C-protein uncoupling, and adenylyl cyclase superactivation. A parallel line of investigation also indicates that opioid tolerance development results from a switch from predominantly opioid receptor G(i alpha) inhibitory to G(beta gamma), stimulatory signaling. As described previously, this results, in part, from the increased relative abundance of G(beta gamma)-stimulated adenylyl cyclase isoforms as well as from a profound increase in their phosphorylation [Chakrabarti, S., Rivera, M., Yan, S.-Z., Tang, W.-J. & Gintzler, A. R. (1998) Mel. Pharmacol. 54, 655-662; Chakrabarti, S., Wang, L., Tang, W.-J. & Gintzler, A, R. (1998) Mel. Pharmacol. 54 949-953], The present study demonstrates that chronic morphine administration results in the concomitant phosphorylation of three key signaling proteins, G protein receptor kinase (GRK) 2/3, beta -arrestin, and G(beta), in the guinea pig longitudinal muscle myenteric plexus tissue. Augmented phosphorylation of all three proteins is evident in immunoprecipitate obtained by using either anti-GRK2/3 or G(beta) antibodies, but the phosphorylation increment is greater in immunoprecipitate obtained with G(beta) antibodies. Analyses of coimmunoprecipitated proteins indicate that phosphorylation of GRK2/3, beta -arrestin, and G(beta) has varying consequences on their ability to associate. As a result, increased availability of and signaling via G(beta gamma) could occur without compromising the membrane content land presumably activity) of GRK2/3. Induction of the concomitant phosphorylation of multiple proteins in a multimolecular complex with attendant modulation of their association represents a novel mechanism for increasing G(beta gamma) signaling and opioid tolerance formation
Targetting CCL25/CCR9: A succesful therapeutic strategy during early chronic murine ileitis
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