Phosphatidylinositides

Phosphoinositol kinases Phosphatidylinositol kinases Phosphatidylinositide kinases... 

D. Phosphatidylinositide Metabolism Affects Ca +-Dependemt Hormone Action ... 

Class II hormones, which bind to cell surface receptors, generate a variety of intracellular signals. These include cAMP, cGMP, Ca +, phosphatidylinositides, and protein kinase cascades. 

I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway, in particular, effects mediated through its effector protein kinase B (PKB, also termed Akt three isoforms) ... 

Figure 7.1 Major signaling pathways relevant to this chapter. Simplified schematic diagram of the major signaling pathways which impinge on mRNA translation I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway II/III. MAP kinases, especially the classical MAP kinase (ERK) pathway and the p38 MAP kinase pathway IV. The mammalian target of rapamycin (mTOR) pathway. Strictly, this diagram shows the rapamycin-sensitive events linked to mTORCl. Selected inhibitors and their sites of action are shown. A numberof components and cross-connections have been omitted for clarity.

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. 

Lithium salts are used in the treatment of bipolar affective disorder (i.e., manic depression) and occasionally in mania (but its slow onset of action is somewhat of a disadvantage in this case). Its mechanism of action is still open to debate, but lithium has effects on brain monoamines, on neuronal transmembrane sodium flux, and on cellular phosphatidylinositides related to second messenger systems. Lithium is administered in two salt forms, lithium carbonate (8.98) and lithium citrate (8.99). Side effects are common and include diarrhea, kidney failure, and drowsiness with tremor. 

Several metabohc pathways lead from phosphatidyl inositol to compounds with second messenger" character (review Liscovitch and Cantley, 1994 Divecha and Irvine, 1995). One main pathway, the formation of diacylglycerol and Ins(l,4,5)P3 from PtdIns(4,5)P2, has already been described in 6.4 and Fig. 6.3. Other compounds of regulatory importance can be formed by phosphorylation at the 3 position of the inositol part of Ptdins (Fig. 6.9). The reaction is catalyzed by a class of enzymes known as phosphatidylinositide 3-kinases (P13-kinases). The P13-kinases phosphorylate various phosphatidyl inositol compoimds at the 3 position. For example, PtdIns(3,4,5)P3, produced by 3 phosphorylation of Ptdlns(4,5)P2, has an important function as an intracellular messenger (see 6.6.2). 

Phosphatidic acids Phosphatidylcholines Phosphatidylserines Phosphatidylglycerols Phosphatidylethanol amines Phosphatidyl inositols Phosphatidylinositides Cardiolipins... 

Karliner JS, Kagiya T, Simpson PC. 1990. Effects of pertussis toxin on alpha 1-agonist-mediated phosphatidylinositide turnover and myocardial cell hypertrophy I neonatal rat ventricular myocytes. Experientia (Basel) 46 81-84. 

PKC is a serine/threonine protein kinase comprised of at least 11 isozymic forms (Nishizuka 1995 Liu and Heckman 1998). These isozymic forms have been classified as atypical, classical, and novel. Classical PKCs (a, pi, pH, and y) are activated by Ca2+, DAG, phosphatidylserine (PS), and the tumor promoter phorbol 12-myristate 13-acetate (PMA). Novel PKCs (6, e, r, i, and 0) are activated by DAG, PS, and unsaturated fatty acids, while atypical PKCs (C, A, and 0 are insensitive to DAG but are activated by PS and phosphatidylinositides (reviewed in Liu and Heckman 1998 Newton and Johnson 1998 Nakanishi et al. 1993). PKCs have been implicated in a wide variety of cellular responses, including growth, differentiation, gene expression, angiogenesis, contractility, and vesicle trafficking (Nishizuka 1995). 

Wang, P., Kitchens, R.L., Munford, R.S., 1998, Phosphatidylinositides bind to plasma membrane CD14 and can prevent monocyte activation by bacterial lipopolysacharide, J. Biol. Chem. 273 24309-24313. 

Ptdlns is the most abundant phosphatidylinositide in cells it constitutes about 90% of the inositol lipids in cell membranes. The other six mono- and bis-phosphorylated Ptdlns make up the remaining 10% with PtdIns(4)Pj and PtdIns(4,5)P2 constituting up about 9% of the lipid pool, each contributing different amounts depending on the tissue. The remaining five lipids make up 1%. PtdIns(3)Pi or PtdIns(5)Pi contribute about 0.4%, and the 3-lipids jointly constitute about 0.1%. These numbers vary slightly from cell to cell (Stephens et al., 2000 Vanhaesebroek et al., 2001), however, it is clear that the quantitatively minor inositol lipids Ptd(4,5)P2 and the 3-phosphorylated lipids play critical roles in signal transduction (Stephens et al., 2000 Toker and Cantley, 1997 Vanhaesebroek et al., 2001). 

Munnik, T., Irvine, R.F. and Musgrave, A., 1994, Rapid turnover of phosphatidylinositol 3-phosphate in the green alga Chlamydomonas eugametos signs of a phosphatidylinositide 3-kinase signaling pathway in lower plants Biochem. J. 298 269-273. 

Brunskill NJ, Stuart J, Tobin AB, Walls J, Nahorski S. Receptor-mediated endocytosis of albumin by kidney proximal tubule cells is regulated by phosphatidylinositide 3-kinase. J. Clin. Invest. 1998 101 2140-2150. 

ZHANG J, King WG, Dillon S, Hall A, FEIG L, RITTENHOUSE SE. Activation of platelet phosphatidylinositide 3-kinase requires the small OTP-binding protein Rho. JBiol Chem 268 22251-22254, 1993. 

W. Yu, J. Cassara, and P.F. Weller, Phosphatidylinositide 3-kinase localizes to cytoplasmic lipid bodies in human polymorphonuclear leukocytes and other myeloid-derived cells. Blood, 2000, 95, 1078-1085. 

Rgu re 14.23 Action of a lipid kinase in insulin signaling. Phosphorylated IRS-1 and IRS-2 activate the enzyme phosphatidylinositide 3-kinase, an enzyme that converts PIP into PIPj,... 

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