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Phosphoinositide and Phospholipid Phosphorylation and Hydrolysis Pathways —Organophosphate and Organochlorine Pesticides Effects

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Phosphoinositide and Phospholipid Phosphorylation and Hydrolysis Pathways —Organophosphate and Organochlorine Pesticides Effects Advances in Biological Chemistry, 2013, 3, 22-35 ABC http://dx.doi.org/10.4236/abc.2013.33A004 Published Online June 2013 (http://www.scirp.org/journal/abc/) Phosphoinositide and phospholipid phosphorylation and hydrolysis pathways —Organophosphate and organochlorine pesticides effects Teresa Fonovich1, Gladis Magnarelli2,3 1Escuela de Ciencia y Tecnología. Universidad Nacional de San Martín, San Martín, Buenos Aires, Argentina 2Instituto Multidisciplinario de Investigación y Desarrollo de la Patagonia Norte (IDEPA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional del Comahue, Neuquén, Argentina 3Facultad de Ciencias Médicas, Universidad Nacional del Comahue, Cipolletti, Río Negro, Argentina Email: [email protected] Received 25 April 2013; revised 30 May 2013; accepted 10 June 2013 Copyright © 2013 Teresa Fonovich, Gladis Magnarelli. This is an open access article distributed under the Creative Commons Attri- bution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT phosphatidylinositol (PtdIns). They consist of negatively charged molecules whose amounts present in eukaryotic Phospholipid and phosphoinositide phosphorylation cells represent less than 10% of the total phospholipids. pathways have been shown to be of crucial impor- Phosphhoinositides include tance on producing lipid mediators. The earlier find- phosphatidylinositol-3-phosphate (PtdIns-3-P), ings reported on lipid molecules playing roles in dif- ferent metabolic pathways used to assign them the phosphatidylinositol-4-phosphate (PtdIns-4-P), exclusive role of second messenger generators. Seve- phosphatidylinositol-5-phosphate (PtdIns-5-P), ral researchers have recently described how direct in- phosphatidylinositol-3,5-bisphosphate (PtdIns-3,5-P2), teraction of phospholipids and phosphoinositides with phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), molecules or organelles, without the need for produ- phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P2), cing second messenger molecules, is responsible for and phosphatidylinositol-3,4,5-trisphosphate(PtdIns-3,4,5- their mechanism of action. Organophosphate and or- P3). These molecules are involved in different cellular ganochlorine pesticide toxicity mechanisms have been processes as signal transduction (which was the one dis- extensively studied in relation to their well known covered in the first place), intracellular membrane traf- effects on cholinesterase activities and on the alterations ficking, exo- and endo-cytosis, nuclear events, cytoske- of electric activity in the nervous system of different leton remodeling, cell growth, cell polarity, etc. [1,2]. organisms respectively. There is little but consistent Major similarities between mammalian, yeast and higher evidence that some compounds, including in both plant phosphoinositide signaling reveal the early ap- groups of pesticides, are also able to interact with pho- pearance and evolutionary conservation of this language. spholipid and phosphoinositide phosphorylation pa- However, there have also been found major differences thways in several organisms and tissues. The present that suggest that organisms may have evolved different review consists of an actualization of basic research PtdIns-4-P and PtdIns-4,5-P2 functions [3]. The aim of on phospholipid and phosphoinositide phosphoryla- the present review is to report an actualization of both tion and hydrolysis pathways, as well as a description the basic research on phospholipid and phosphoinositide of some reported evidences for the effects of the above phosph- orylation and hydrolysis pathways and some mentioned pesticides on them. effects of organophosphate and organochlorine pesticides that have been described on these pathways. Keywords: Phosphatidylinositol-4,5-biphosphate; Phosphoinositide; Phospholipid; Phosphatidylcholine; 2. PHOSPHOLIPIDS AND Organophosphate Pesticides; Organochlorine Pesticides PHOSPHOINOSITIDES 2.1. Pathways Involving Phosphorylation and 1. INTRODUCTION Hydrolisis Phosphoinositides are the phosphorylated derivatives of The enzymes responsible for the phosphorylation and OPEN ACCESS T. Fonovich, G. Magnarelli / Advances in Biological Chemistry 3 (2013) 22-35 23 dephosphorylation of phosphoinositides are different ki- monstrated that only a restricted pool of PtdIns-4-P at the nases and phosphatases. PtdIns-5-kinase and PtdIns-4- trans-Golgi network (TGN) is required for Golgi integ- kinase catalize the phosphorylation of PtdIns-4-P and rity. In mammalian cells, the stress-activated mitogen- PtdIns-5-P thus producing PtdIns-4,5-P2. On the other activated protein kinase (MAPK) p38 plays a critical role hand, phospholipase C (PLC) is the phosphatase which in transmitting nutrient signals to the phosphoinositide substrate is PtdIns-4,5-P2 and produces, as the cones- signaling machinery at Golgi and the ER. quence of an appropriate stimulus, the second messenger Regulation of PtdIns-3-P has a role in early endosomal molecules: diacylglycerol (DAG) and Inositol-1,4,5-tris- traffic and autophagy. PtdIns-3-P is synthesized by class phosphate (InsP3). A protein family of phosphoinosi- III PI 3-kinase Vps34 in yeast and mammals and Vps34 tide-3-kinases is responsible for the production of PtdIns- forms specific complexes with co-factors. Phospholipase 3-P, PtdIns-3,4-P2, and PtdIns-3,4,5-P3 [4]. All of the D1 (PLD1) and mTOR complex 1 (mTORC1) are invo- 3-phosphorylated phosphoinositides act as intracellular lved in metabolic signaling of PtdIns-3-P. Several phos- signaling molecules [5]. phatases belonging to the myotubularin (MTM) and The levels of PtdIns-3-P, PtdIns-4-P, PtdIns-3,5-P2 myotubularin-related protein (MTMR) family are able to and PtdIns-4,5-P2 are relatively stable at specific mem- dephosphorylate PtdIns-3-P. Regulation of PtdIns-3,5-P2 branes where they are distributed under normal cell has a function in late endosomal dynamics and in auto- growth conditions. These phosphoinositides are concen- phagy and its synthesis and turnover are tightly coupled. trated in different cell membranes. PtdIns-3-P and PtdIns- Different authors’ results suggest that endolysosome lo- 4-P are concentrated at endosomes and Golgi membranes calized, mucolipin transient receptor potential (TRPML) respectively, while PtdIns-3,5-P2 concentrates at late en- 2+ channels, are PtdIns-3,5-P2 effectors that control Ca - docytic compartments and PtdIns-4,5-P2 at the plasma dependent membrane dynamics in response to extracel- membrane. Effector proteins that bind phosphoinositides lular stimuli. Both 5-phosphatases and myotubularins govern the selective distribution of these phospholipids dephosphorylate PtdIns-3,5-P2. While the first ones gen- in different membranes. On the other hand, PtdIns- erate PtdIns-3-P, the second enzymes dephosphorylate 3,4-P2, and PtdIns-3,4,5-P3 concentration is more unsta- this molecule 3-position of the inositol headgroup to pro- ble, they are synthesized in response to extracellular sti- duce PtdIns [6]. muli and are involved in cell proliferation and survival PtdIns-5-P is known for its role in nuclear signaling [6]. Shenker et al. [7] have previously reported these and membrane dynamics. This molecule can be synthe- kinds of responses for PtdIns-3,4,5-P3 and proposed that sized by phosphatases via dephosphorylation of PtdIns- this phosphoinositide may represent a potent target for 3,5-P2 or PtdIns-4,5-P2, depending on the organism. Re- developing therapeutic approaches to down regulate mast cently, mammalian type I and II PtdIns-4-phosphatases cell function and, in turn, reduce the severity of mast cell have been identified that generate PtdIns-5-P in vitro us- dependent disease. ing PtdIns-4,5-P2 as substrate. PtdIns-5-P is able to bind Cell migration is a dynamic and highly orchestrated to the nuclear adaptor denominated inhibitor of growth cellular process, which is involved in a variety of mor- protein-2 (ING2) that regulates chromatin rearrangement phogenic events during organ and tissue development. in response to stress. But there is also increasing evi- Studies on disruption of Golgi were accompanied by the dence that PtdIns-5-P may play an important role in re- inhibition of cell migration and allowed researchers to gulating membrane dynamics in both endocytic and exo- conclude that Golgi has an active role in cell migration, cytic processes [6]. in association with the centrosome, when its structural Phosphatidylcholine (PC) is the principal source of integrity is intact. There is increasing evidence for the free fatty acids (FFA) which in turn may act as second role of signal transduction in regulating the Golgi during messengers or as precursors of bioactive molecules like cell migration. GOLPH3 is a Golgi protein that binds prostaglandins, thromboxanes and leukotrienes. Polyun- PtdIns-4-P and depends on this phosphoinositide for its saturated fatty acids (PUFA) derive from the sn-2 glyc- Golgi localization. Dippold et al. [8] have recently dem- erol carbon of cell membrane phospholipids and are onstrated that GOLPH3 binds myosin (thus connecting precursors of a number of eicosanoids. Other FFA such Golgi to F-actin), as well as the need of this linkage for as docosahexaenoic acid (DHA), docosapentaenoic acid the normal Golgi morphology and trafficking function. (DPA), are precursors of various other lipid mediators. GOLPH3 was also shown to regulate the mammalian Phospholipase D (PLD) is the enzyme located
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