Second messengers phosphate

Family of enzymes phosphorylating phosphatidylinositol (Ptdlns), PtdIns(4)phosphate, and PtdIns(4,5)phosphate in the 3-position. The Ptdlns(3 phospholipids are second messengers in processes like cell growth, cytoskeletal rearrangement, and vesicular transport. PI 3-kinases are heterodimers composed of a catalytic and a regulatory subunit. The enzymes are activated by insulin, many growth factors, and by a variety of cytokines. Their activity can be inhibited by wortmannin and LY294002. 

The cAMP molecule serves as the second messenger, which carries out the effects of the hormone inside the cell. The primary function of cAMP is to activate protein kinase A. This kinase then attaches phosphate groups to specific enzymatic proteins in the cytoplasm. The phosphorylation of these enzymes enhances or inhibits their activity, resulting in the enhancement or inhibition of specific cellular reactions and processes. Either way, cellular... 

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+. 

FIGURE 20-7 Pathways of inositol phosphate metabolism. Note that the metabolism of the second messenger I(1,4,5)P3 is shown to the left of the dashed line, while the interconversions of the higher inositol phosphates are shown to the right of the dashed line. Only the quantitatively major established pathways are depicted. Li+ is known to block the dephosphorylation reactions indicated by the (black) bars. Numbers refer to the following enzymes 1, inositol polyphosphate 5-phosphatase (I) 2, inositol polyphosphate 1-phosphatase 3,I(1,4,5)P3 3-kinase 4, inositol polyphosphate 4-phosphatase 5, inositol polyphosphate 3-phosphatase 6, inositol monophosphate phosphatase 7, I(1,3,4)P3 6-kinase/I(3,4,5,6)P4 1-kinase 8, Ipmk 9, DIPP 10, IP6 kinase 11, Ipk 1 12, MIPP 13, PP-IP5 kinase. 

Spiegel, S., 1999, Sphingosine 1-phosphate a prototype of a new class of second messengers. J. Leukoc. Biol. 65 341-4. 

Ohvera, A. and Spiegel, S., 1993, Sphingosine 1-phosphate as a second messenger in cell proliferation induced by PDGF and ECS mitogens, Nature (London) 365 557-560. 

Glycerophospholipids are used for membrane synthesis and for producing a hydrophilic surface layer on lipoproteins such as VLDL. In cell membranes, they also serve as a reservoir of second messengers such as diacylglycerol, inositol 1,4,5-triphosphate, and arachidonic acid. Their structure is similar to triglycerides, except that the last fatty acid is replaced by phosphate and a water-soluble group such as choline (phosphatidylcholine, lecithin) or inositol (phosphatidyl-inositol). 

An additional phosphorylation (enzyme phosphatidylinositol-4-phosphate kinase 2.7.1.68) finally provides phosphaditylino-sitol-4,5-bisphosphate (PIP2, Ptdlns(4,5)P2). PIP2 is the precursor for the second messengers 2,3-diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (InsPa, IP3 see p. 367). 

An additional action of Li" is interruption of the phosphatidylinositide cycle through an inhibitory action on inositol phosphate metabolism. By this mechanism, depletion of membrane inositol and the phosphoinosi-tide-derived second-messenger products diacylglycerol and inositol triphosphate ultimately reduces signaling through receptor systems dependent on the formation of these products. It is presently unclear to what extent inhibition of inositol phosphate metabolism contributes to the therapeutic properties of Li+ in bipolar patients. 

The last three sources are transported into the cell via inositol transporter [T]. Inositol combines with cytidine monophosphate phosphatidic acid [GMPPA] to be converted to PI, which is then phosphorylated to phos-phatidylinositol phosphate [PIP] and to PIP2 to be reused to form the PI cycle-derived second messengers IP3 and DAG [Kofman and Belmaker 1993]. 

The picture that has emerged from these studies is of an initial interaction of a stimulus with a matched portion of a receptor protein embedded in the cell membrane (13,65). This initial interaction causes stimulation of the linked G-protein to form cGMP. This is coupled to the reactivity of adenylate cyclase in the cells, leading to increased levels of cAMP, which opens ion channels in the cell membrane. A similar sequence can alternatively activate inositol phosphate as a second messenger. Either odorants, cAMP or cGMP can cause a potential change in the membrane (13,70,71,72). As in hormone-sensitive and neurotransmitter-... 

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