Platelet-activating factor: receptors and signal transduction

Abstract

During the past two decades, studies describing the chemistry and biology of PAF have been extensive. This potent phosphoacylglycerol exhibits a wide variety of physiological and pathophysiological effects in various cells and tissues. PAF acts, through specific receptors and a variety of signal transduction systems, to elicit diverse biochemical responses. Several important future directions can be enumerated for the characterization of PAF receptors and their attendant signalling mechanisms. The recent cloning and sequence analysis of the gene for the PAF receptor will allow a number of important experimental approaches for characterizing the structure and analysing the function of the various domains of the receptor. Using molecular genetic and immunological technologies, questions relating to whether there is receptor heterogeneity, the precise mechanism(s) for the regulation of the PAF receptor, and the molecular details of the signalling mechanisms in which the PAF receptor is involved can be explored. Another area of major significance is the examination of the relationship between the signalling response(s) evoked by PAF binding to its receptor and signalling mechanisms activated by a myriad of other mediators, cytokines and growth factors. A very exciting recent development in which PAF receptors undoubtedly play a role is in the regulation of the function of various cellular adhesion molecules. Finally, there remain many incompletely characterized physiological and pathophysiological situations in which PAF and its receptor play a crucial signalling role. Our laboratory has been active in the elucidation of several tissue responses in which PAF exhibits major autocoid signalling responses, e.g. hepatic injury and inflammation, acute and chronic pancreatitis, and cerebral stimulation and/or trauma. As new experimental strategies are developed for characterizing the fine structure of the molecular mechanisms involved in tissue injury and inflammation, the essential role of PAF as a primary signalling molecule will be affirmed. Doubtless the next 20 years of experimental activity will be even more interesting and productive than the past two decades.

Increased hepatic platelet activating factor (PAF) and PAF receptors in carbon tetrachloride induced liver cirrhosis

“…P latelet activating factor (PAF: 1-O-alkyl-2-acetyl-snglycero-3-phosphocholine), a phospholipid, exerts diverse biological activities in various organs and isolated cells; its actions include platelet secretion and aggregation, bronchoconstriction, synthesis of mediators such as eicosanoids, increased vascular permeability, and systemic hypotension. [1][2][3][4][5][6] PAF acts as a multifunctional soluble proinflammatory agent and as a specific membrane bound adhesion molecule. [6][7][8] While systemic infusion of PAF reduces arterial blood pressure, 9 10 PAF administered via the portal vein increases portal venous pressure both in the intact perfused liver 11 and in the liver in vivo.…”

Regulation of platelet-activating factor receptor gene expression in vivo by endotoxin, platelet-activating factor and endogenous tumour necrosis factor

“…PAF receptor (PAF-R) exists in platelets, neutrophils, monocytes, macrophages and endothelium [15]. PAF-R is a member of the G-protein-coupled receptor superfamily characterized by seven transmembrane domains.…”

“…PAF-R is a member of the G-protein-coupled receptor superfamily characterized by seven transmembrane domains. Activation of PAF-R leads to the activation of several signal-transduction pathways [15,16]. Studies on comparative quantification of PAF-R in organ\tissue are rare, probably because of the technical difficulty of differentiating membrane binding and membrane intercalation of a phospholipid [2,17].…”

Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity

“…PAF has been recognized as an important mediator in the pathogenesis of various intestinal diseases including IBD (inflammatory bowel disease), cholera and necrotizing enterocolitis in newborns [3][4][5][6]. The effects of PAF are mediated through G-protein-coupled receptors expressed in several tissues, including the intestinal mucosa [7], leading to functional changes of numerous signalling molecules such as activation of MAPK (mitogen-activated protein kinase) and NF-κB (nuclear factor κB), induction of biosynthesis of prostaglandins, expression of PLA 2 and release of a variety of cytokines, including IL-8 (interleukin 8), IL-1β and TNFα (tumour necrosis factor α) [8][9][10][11]. Increased PAF has been reported in faeces from patients with ulcerative colitis and Crohn's disease [12].…”