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Platelet-activating Factor Receptor

Platelet-activating factor (PAF), a structurally unusual lipid autacoid possessing an intact 1-O-alkyl glycerophospholipid (GPC) backbone (l-O-alkyl-2-acetyl-s7i-glycero-3-phosphocholin), was originally identified as a pro-inflammatory mediator. PAF, and structurally related GPC oxidatively fragmented at the sn-2 position, function as mediators in a variety of settings including atherosclelosis, neural functions and reproduction. Cloned PAF receptor (PAFR) possesses a typical structure of G protein-coupled receptors (GPCRs) with seven transmembrane helices, and it presumably signals through Gaq/11, Gao, and God, and also GP7. PAFR subtypes have not been identified. PAFR^" mice apparently grow normally. Their phenotypes revealed that the cloned PAFR plays major roles in inflammatory responses including systemic anaphylaxis. PAFR is post-translationally modified by disulfide bonding at C90-C173 and by A^-linked glycosylation at N169. These modifications are required for efficient cell surface expression of PAFR. The Ser and Thr cluster at the Cterminus is phoshorylated upon PAF binding, and this process, presumably catalyzed by G protein-coupled receptor kinase (GRK)-2, seems crucial for homologous desensitization and for facilitated internalization of PAFR (41-A4). Common and downstream desensitization mechanisms are also noted in the PAFR system, including phospholipase Cp3 (PLCp3) phosphorylation by protein kinase C (PKC) and Gq-mediated proteolysis of inositol 1,4,5-trisphosphate (IP3) receptor.