Intracellular Signaling by Phospholipase D as a Therapeutic Target

Authors: Steeed P.M.; Chow A.H.m.

Source: Current Pharmaceutical Biotechnology, Volume 2, Number 3, September 2001 , pp. 241-256(16)

Publisher: Bentham Science Publishers

Abstract:

The pharmaceutical industry has recently focused on intracellular signaling as a means to integrate the multiple facets of complex disease states, such as inflammation, because these pathways respond to numerous extracellular signals and coordinate a collection of cell responses contributing to pathology. One critical aspect of intracellular signaling is regulation of key cell functions by lipid mediators, in particular the generation of a key mediator, phosphatidic acid (PA) via the hydrolysis of phosphatidylcholine by phospholipase D (PLD). Research in this field has intensified, due in part to the recent cloning and partial characterization of the two PLD isoforms in mammalian cells, and this work has contributed significantly to our understanding of events downstream of PA generation. It is these effector functions of PLD activity that make this pathway attractive as a therapeutic target while the biochemical properties of the PLD isozymes make them amenable to small molecule intervention. Recent studies indicate that PA, and its immediate metabolites diacylglycerol and lyso-PA, affect numerous cellular pathways including ligand-mediated secretion, cytoskeletal reorganisations, respiratory burst, prostaglandin release, cell migration, cytokine release, and mitogenesis. This review summarises the data implicating signaling via PLD in these cell functions, obtained from: (i) molecular analyses of PLD / effector interactions, (ii) correlation between PA production and cell responses, (iii) experimental manipulation of PA levels, (iv) inhibition of PLD regulators, and (v) direct inhibition of PA production. The utility of targeting PLD signaling for the treatment of acute/chronic inflammation and other indications is discussed in light of these data.

Keywords: intracellular signaling; phospholipase d; therapeutic traget; ligand-mediated secretion; cytoskeletal reorganisations; respiratory burst; prostaglandin release; cytokine release; mitogenesis; pld catalysis; pld isoform

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389201013378644

Publication date: 2001-09-01

• Current Pharmaceutical Biotechnology aims to cover all the latest and outstanding developments in Pharmaceutical Biotechnology. Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics in both pre-clinical and clinical areas of Pharmaceutical Biotechnology. Current Pharmaceutical Biotechnology is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments.

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• In this Subject: Nutrition & Food ,  Biotechnology ,  Pharmacology
• By this author: Steeed P.M. ;  Chow A.H.m.

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