Second messengers phosphatidylinositol

Maehama, T., and Dixon, J.E. (1998). The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273, 13375-13378. 

Blondeau, F, Laporte, J, Bodin, S, Superti-Furga, G, Payrastre, B and Mandel, JL (2000) Myotubularin, a phosphatase deficient in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Hum Mol Genet, 9, 2223-2229. 

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 inositol is present in ph osphatidylinositol as the stereoisomer, myoinositol (Figure 14—8). Phosphatidylinositol 4,5-hisphosphate is an important constituent of cell membrane phosphohpids upon stimulation by a suitable hormone agonist, it is cleaved into diacylglycerol and inositol trisphosphate, both of which act as internal signals or second messengers. 

PTHrP). The receptor signal is mediated by G proteins that activate adenylyl cyclase and the phosphatidylinositol-calcinm second-messenger system. Mntations of PTHRl are associated with abnormalities of development related to altered PTHrP ligand binding. PTHrP is a key paracrine peptide responsible for osteochondrogenesis dnring fetal development (55,56). 

Phosphatidylcholine (lecithin) is the most abundant phospholipid in membranes. Phosphatidylethanolamine (cephalin) has an ethanolamine residue instead of choline, and phosphatidylserine has a serine residue. In phosphatidylinositol, phosphatidate is esterified with the sugarlike cyclic polyalcohol myo-inositol. A doubly phosphorylated derivative of this phospholipid, phosphatidylinositol 4,5-bisphosphate, is a special component of membranes, which, by enzymatic cleavage, can give rise to two second messengers, diacylglycerol (DAG) and inositol l,4,5trisphosphate (InsPsi see p.386). 

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). 

Type Gq G proteins activate phospholipase C [4]. This enzyme creates two second messengers from the double-phosphorylated membrane phospholipid phosphatidylinositol bisphosphate (PinsP2), i. e., inositol 1,4,5-tris-... 

Figure 14-3. Signaling through protein kinase C (PKC). Activated phospholipase C cleaves the inositol phospholipid PIP2 to form both soluble (IP3) and membrane-associated (DAG) second messengers. DAG recruits PKC to the membrane, where binding of calcium ions to PKC fully activates it. To accomplish this, IP3 promotes a transient increase of intracellular concentration by binding to a receptor on the endoplasmic reticulum, which opens a channel allowing release of stored calcium ions. PIP2, phosphatidylinositol 4,5-bisphosphate DAG, diacylglycerol PLC, phospholipase C IP3, inositol trisphosphate.

Lithium inhibits inositol monophosphate and decreases brain levels of inositol. Belmaker s group [see Levine et ah. Chapter 9, in this volume) showed a selective therapeutic effect of inositol in patients with either depression or panic disorder. Because of the possible importance of the second-messenger system of the phosphatidylinositol [PI) cycle in mood regulation, and because of its influence by lithium, it would be of future in-... 

I nositol is a simple substance present normally in the diet at about 1 g/day and is an isomer of glucose. The phosphatidylinositol (PI) cycle is an important second messenger system for several brain neurotransmitters (Figure 9-1). Receptor (R) stimulation by an activator (A) leads to breakdown of membrane phosphatidylinositol 4,5-biphosphate (PIP2) to... 

A second class of serpentine receptors are coupled through a G protein to a plasma membrane phospholipase C (PLC) that is specific for the plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (see Fig. 10-15). This hormone-sensitive enzyme catalyzes the formation of two potent second messengers diacyl-glycerol and inositol 1,4,5-trisphosphate, or IP i (not to be confused with PIP3, p. 431). 

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