The Eicosanoids in Cellular Signaling

As we have noted in chapter 1, the eicosanoids provide a good example of an alternative, more complex mode of action. These compounds are synthesized within cells, and they produce many of their biological effects by interacting with intracellular target proteins. Like non-esterified arachidonate, the eicosanoids appear 

The purpose of the present chapter is to provide an overview of these distinct and complementary roles of the arachidonate cascade, intracellular and transcellular. We will first consider a series of messenger functions that arachidonate metabolites may serve within cells. We will turn next to the transport mechanisms used by the eicosanoids to exit cells and to gain access to transmembrane receptors present on the surface of cells nearby. Finally, we will briefly discuss the molecular structures of the eicosanoid receptors, their transduction mechanisms and some of their physiological and pharmacological properties. 

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Eicosanoids derived from the n-3 PUEAs are up to 100-fold less biologically potent for inducing pro-inflammatory cellular responses than those derived from AA (121, 122). It is proposed that dietary n-3 PUEAs act by two different mechanisms to control the amount of n-6 eicosanoids maintained in tissues first, by competing for incorporation into tissue lipid esters, thus reducing the rate of tissue formation of active n-6 eicosanoids and second, by forming weaker n-3 eicosanoids (123, 124) that compete at cellular receptor sites and diminish signaling by eicosanoids derived from n-6 PUEAs. As a result, diets with n-3 PUFAs create conditions that reduce the formation and constrain the function of active n-6 eicosanoids in stimulated cells (116). 

There are many unanswered questions about the dual role that ether lipids serve as membrane components and as cellular signaling molecules. Although it is clear that arachidonic acid is closely associated and tenaciously retained by ether lipids in membranes, even in essential fatty acid deficiency, much remains to be elucidated about the enzymatic systems and regulatory controls that affect the release of this sequestered pool of arachidonic acid for its subsequent conversion to bioactive eicosanoid metabolites. The significance of ether lipids as a dietary nutrient has received little attention even though they occur in a variety of foods and it is known that ether lipid supplements are readily incorporated into cellular lipids. 

AA is the substrate for most eicosanoid mediators produced by mammalian cells. It is also present in large amounts in phosphatidylinositol, a PL that functions in membrane signal transduction. The need for AA is probably the main reason why LA is essential for health. PUFA, especially of the n-3 type, are preferentially incorporated at the 2-position of most cell membrane PL and are considered to play an important role in both cell membrane integrity and function. Cellular stimulation leads to activation of phospholipase A, followed by mobilization of the FA on the 2-position of cell membrane PL. The types of these FA determine, to a great extent, the types of cyclooxygenase and lipoxygenase products. 

Figure 12.2. Alternate pathways of arachidonic acid release (a), and cellular locations of enzymes involved in eicosanoid formation (b). a Arachidonic acid may be directly released by phospholipase (PLA2), or alternatively by the successive action of phospholipase C (PLC) and diacylglycerol (DAG) lipase, b The major mechanism of release involves a cytosohc phospholipase A2 (CPLA2). An increase of Ca in response to an extrinsic signal causes binding of cPL A2 to the nuclear membrane. Cyclooxygenase (COX) and Lipoxygenase (LOX) form their respective intermediates, which are further processed by cytosolic enzymes to prostaglandins (PG), thromboxanes (TG), and leukotrienes (LT), respectively.

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