Metabolism of Polyunsaturated Fatty Acids and its Effect on Neural Membranes Receptors

In neural membranes DHA mainly incorporates in ethanolamine plasmalogen (PlsEtn) and phosphatidylserine (PtdSer), whereas majority of ARA incorporates into phosphatidylcholine (PtdCho). From PlsEtn and PtdSer, DHA is released by the action of plasmalogen-selective PLA2 and PtdSer hydrolyzing PLA2, respectively [12-15]. The released DHA is metabolized into resolvins and neuroprotectins by 15-lipoxygenase [16-18]. These mediators are collectively known as docosanoids. They have anti-inflammatory and antiapoptotic properties and are involved in neuroprotection. In addition, docosanoids have antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory effects [4,16-18]. In contrast, ARA is released from neural membrane PtdCho by cPLA2 and metabolized to prostaglandins, leukotrienes and thromboxanes. These metabolites are collectively known as eicosanoids. These metabolites have prothrombotic, proaggregatory, and proinflammatory properties. The levels of eicosanoids and docosanoids in neural and non-neural tissues are partly regulated by diet (see below).

In brain tissue, neurotransmitters not only carry information from one brain cell to another, but also transfer information from plasma membrane to nucleus via cytoplasm. This process is facilitated by other non-nuclear subcellular organelles, such as mitochondria and endoplasmic reticulum. Neuronal and glial cell membrane contains a series of receptors, which interact with neurotransmitters. Interactions of neurotransmitters (biogenic amine, glutamate, and cannabinoid) with their receptors result in enrichment of neural membrane glycerophospholipid metabolism through the stimulation of PLA2 and PLC. Through cross talk between glutamate and biogenic amine receptors, the message is transferred from neural cell surface to the nucleus. This transfer of message is essential for maintaining neuronal and glial cell plasticity and growth. It should be noted that the products of one phospholipase modulate the activity of other phospholipase. Thus, the stimulation of PLC through biogenic amine receptor hydrolyzes PtdIns(4,5)P2 and generates diacylglycerol (DAG). DAG activates protein kinase C (PKC), which in turn activates PLA2 and PLD (Figure 2). PtdIns(4,5)P2

stimulates PLA2 and inhibits PLD [19-20]. Similarly, generation of ARA and eicosanoids activate PLD [21].

Figure 2. Degradation of neural membrane glycerophospholipid by receptor mediated phospholipases A2 and C. Serotonin receptors (5HT2) are linked to the degradation of PtdIns-4,5-P2, dopamine (DA) receptors are linked to PLA2 through G protein, dopamine receptors are also linked to Adenylyl cyclase and glutamate (GLU) receptors are linked to PLA2 through G protein independent mechanisms. Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2); inositol 1,4,5-trisphosphate (Ins^3); phosphatidylcholine (PtdCho); phosphatidylethanolamine (PtdEtn); ethanolamine plasmalogen (PlsEtn); lyso-phosphatidylcholine (lyso-PtdCho); lyso-plasmalogen (lyso-PlsEtn); phospholipase C (PLC); cytosolic phospholipase A2 (cPLA2); plasmalogen-selective phospholipase A2 (PlsEtn-PLA2); Adenylyl cyclase (AC); protein kinase A (PKA); protein kinase C (PKC); arachidonic acid (ARA); diacylglycerol (DAG); monoacylglycerol (MAG); docosahexaenoic acid (DHA); reactive oxygen species (ROS); free fatty acid (FFA); cAMP response element binding protein (CREB); and cAMPregulated phosphoprotein of 32,000 kDa (DARPP-32).

Figure 2. Degradation of neural membrane glycerophospholipid by receptor mediated phospholipases A2 and C. Serotonin receptors (5HT2) are linked to the degradation of PtdIns-4,5-P2, dopamine (DA) receptors are linked to PLA2 through G protein, dopamine receptors are also linked to Adenylyl cyclase and glutamate (GLU) receptors are linked to PLA2 through G protein independent mechanisms. Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2); inositol 1,4,5-trisphosphate (Ins^3); phosphatidylcholine (PtdCho); phosphatidylethanolamine (PtdEtn); ethanolamine plasmalogen (PlsEtn); lyso-phosphatidylcholine (lyso-PtdCho); lyso-plasmalogen (lyso-PlsEtn); phospholipase C (PLC); cytosolic phospholipase A2 (cPLA2); plasmalogen-selective phospholipase A2 (PlsEtn-PLA2); Adenylyl cyclase (AC); protein kinase A (PKA); protein kinase C (PKC); arachidonic acid (ARA); diacylglycerol (DAG); monoacylglycerol (MAG); docosahexaenoic acid (DHA); reactive oxygen species (ROS); free fatty acid (FFA); cAMP response element binding protein (CREB); and cAMPregulated phosphoprotein of 32,000 kDa (DARPP-32).

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