Chemokine receptor activation

Chemokine Receptor Activation by HIV Envelope Protein gpl20... 

Brelot A, Heveker N, Montes M, Alizon M. Identification of residues of CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities. J Biol Chem 2000 275(31) 23736-23744. 

Richmond A, Fan GH, Dhawan P, Yang J. How do chemokine/chemokine receptor activations affect tumorigenesis Novartis Found Symp 2004 256 74-89. 

Aminothiazolo[5,4-, pyrimidine 431 is claimed to be a modulator of chemokine receptor activity. The compound is claimed to be useful for treatment of chemokine-mediated diseases such as psoriasis <2001W00158960>. 

MIP-la chemokine receptor activity modulators consisting of 4-fluorobenzyl-piperidinylamide ureas, (IV), prepared by Duncia (4) and sulfonic acid derivatives, (V), prepared by Hayward (5) were effective in treating inflammation and autoimmune disorders including asthma and allergic disorders. 

Chemokine receptor activation leads to the generation of a complex cascade of cellular events, including the generation of inositol triphosphates, the release of intracellular calcium, and the activation of protein kinase C. The release of the GaijSy subunits from Gai has been described as an essential step in this process (25). However, the release from Gas or Gaq does not result in induction of chemo-taxis, suggesting that the subunits are necessary but not sufficient to induce cell migration and that Gai itself plays some role in the process (26). 

Activation of the chemokine receptor leads to rapid activation of phosphoinositide-spe-cific phospholipases, which leads to inositol-1,4,5-triphosphate formation and a transient rise in intracellular calcium (18). Phospholipase C (PLC) isoforms that are involved in chemokine receptor activation become activated by direct interaction with the J3y subunits. In addition to its interaction with PLCs, the j3y subunits also interact with the type phosphoinositol 3 kinase y (PISKy), and activation of this enzyme results in the formation of PtdIns(3,4,5)P3 (17). Mice that do not express PI3Ky have severely impaired chemo-kine-stimulated signal transduction, and PKB is not activated, suggesting an important role for this pathway in the chemotactic process (27-29). Although leukocytes isolated from these mice showed a decrease in cell chemo-taxis, the response is not completely lost, and under conditions of complete PI3Ky inhibition, neutrophils can still chemotax in response to chemokines (30). 

Balakin, K. V., Ivanenkov, Y. A., Tkachenko, S. E., Kiselyov, A. S., and Ivachtchenko, A. V. (2008) Regulators of chemokine receptor activity as promising anticancer therapeutics. Curr. Cancer Drug Targets 8, 299-340. 

Viral Chemokine Receptor Activities and Receptor-L and Selectivity... 

The ultimate cellular response following chemokine receptor activation is chemotactic migration, i.e., chemotaxis of cells (Moser, Wolf, Walz, Loetscher, 2004). Traditionally, this is measured with an in vitro transwell assay, where suspension cells (leukocytes) are placed in droplets on top of a filter, which on its lower side is in contact with medium containing... 

Salanga, C. L., O Hayre, M., Handel, T. (2009). Modulation of chemokine receptor activity through dimerization and crosstalk. Cellular and Molecular Life Sciences, 66(8), 1370-1386. 

Small molecule receptor agonists and antagonists of CCR3 provide insight into mechanisms of chemokine receptor activation. The Journal of Biological Chemistry, 282, 27935-27943. 

Understanding of the molecular basis of chemokine receptor activation has been aided considerably by the determination of the crystal structure of the related GPCR bovine rhodopsin (Palczewski et al., 2000), allowing... 

The subsequent signaling events downstream of chemokine-mediated G-protein activation are complicated. It has already been mentioned that signaling events from chemokine receptors are commonly inhibited by pertussis toxin, leading to the assumption that chemokine receptors are Ga linked. One of the most rapid occurrences following chemokine receptor activation is a rise in the intracellular calcium concentration dCa +]i), and this has commonly been used as a measurement for the functional response of receptor activation. Increases in [Ca " "] are mediated via the jSy subunit of the G-protein that activates phospholipase CjS, leading to 1) hydrolysis of phosphatidylinositol to IP3 and 2) DAG formation, which respectively induce the release of Ca + from intracellular stores and subsequent activation of PKC. PKC activation is necessary for certain leukocyte responses, such as neutrophil respiratory burst (Li et al., 2000), and it also plays a role in receptor phosphorylation, leading to desensitization and internalization, which will be discussed later. 

Ebden M, Meghani R, Cook P, Steele AR, Cheema J, Singh LL (2004) Pyrimidine derivatives as modulators of chemokine receptor activity W02004018435... 

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