Other Lipid Messengers

The second important regulatory function of diacylglycerol is stimulation of protein kinase C (see 7.7). Protein kinase C is a protein kinase occurring in almost all cells, and has a regulating effect on many reactions of the cell. Characteristic for protein kinase C is its stimulation by Ca, diacylglycerol and phosphatidyl serine. 

In addition to the membrane associated messenger substances diacylglycerol and PtdIns(3,4,5)P3 mentioned above, other hpoplulic compoimds have also been identified that are specifically formed in the process of signal transduction and which function as messenger substances (review Liscovitch and Cantely, 1994). Two such compounds are presented here  

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Specific lipid messengers are cleaved from reservoir phospholipids by phospholipases upon activation by various stimuli. These stimuli include neurotransmitters, neurotrophic factors, cytokines, membrane depolarization, ion channel activation and others. Lipid messengers regulate and interact with multiple other signaling cascades, contributing to the development, differentiation, function, protection and repair of the cells of the nervous system. 

Reports that AA is released primarily by G-protein-mediated PLA2 activation remain to be confirmed [84, 85]. In addition, modulation of PLA2 by Ca2+ and protein kinase needs to be better defined. It is clear that NMDA receptor activation promotes the release of AA [86], and that a variety of eicosanoids are then generated (Fig 33-2,33-3). The modulatory events that channel AA towards specific eicosanoids are not understood. The endocannabinoid family of lipid messengers will remain an active focus of interest because of the growing evidence of their actions in synaptic function, learning, memory, and other forms of behavior [56,87]. 

Special tasks. Some lipids have adopted special roles in the body. Steroids, eicosanoids, and some metabolites of phospholipids have signaling functions. They serve as hormones, mediators, and second messengers (see p.370). Other lipids form anchors to attach proteins to membranes (see p.214). The lipids also produce cofactors for enzymatic reactions—e.g., vitamin K (see p.52) and ubiquinone (see p.l04). The carotenoid retinal, a light-sensitive lipid, is of central importance in the process of vision (see p.358). 

Ptdins 3-kinases and the lipid messengers they produce play an important role in growth regulation and in several other cellular responses, including the insulin response (Chapter 8). The Class 1 Ptdins 3-kinases are regulated by Ras. Ras-GTP binds to the regulatory subunit of the kinase. Cells expressing Ras mutants that can not interact with Ptdins 3-kinases have lost certain responses. 

Y. Nishizuka. 2 They are activated by diacylgjycerol (DAG) and Ca2+. Diacylglycerol is formed from phosphatidylinositol-4, 5 -P2 by phospholipase C. The other product of this reaction is IP3, a lipid messenger, releasing Ca + from intracellular stores. The protein kinase C family has at least 11 members the largest amounts of protein kinase C are present in the brain. Some routes of PKC signalling in the brain are indicated in Fig. 7.5 there are others. 

Of the different classes of non-protein kinases, the development of inhibitors of lipid kinases has received by far the most attention. A majority of this work centers on inhibitors of phosphatidylinositol kinases, which reflects the important role that phosphatidylinositols play as second messengers. In this section, we review inhibitors of PI3K and related kinases, as well as inhibitors of other phosphatidyl inositol kinases. We also discuss sphingosine kinase inhibitors and we end this section with a brief summary of inhibitors of other lipid kinases. 

The other activity associated with transmembrane receptors is phospholipase C. Phosphatidyl inositol is a membrane phospholipid that after phosphorylation on the head group is found in the membrane as a phos-photidylinostitol bis phosphate. Phospholipase C cleaves this into a membrane associated diacylglycerol (the lipid part) and inositol trisphosphate (IP3, the soluble part). Both play a later role in elevating the level of the second messenger, Ca2+. 

Inositol lipids can serve as mediators of other cell functions, independent of their role as precursors of second messengers 358... 

Moreover,bioactive lipids maybe considered dual messengers they modulate cell functions as messengers and they become part of the response of the nervous tissue to injury, broadly referred to as the inflammatory response. This response occurs in ischemia-reperfusion damage associated with stroke, various forms of neurotrauma, infectious diseases and neurodegenerative diseases such as Alzheimer s disease. Inflammation in the nervous system differs from that in other tissues. If the blood-brain barrier is broken, blood-borne inflammatory cells (e.g. polymorphonuclear leukocytes, monocytes, macrophages) invade the intercellular space and glial cells are activated, particularly microglia, which play a prominent role in the inflammatory response. These responses may... 

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