Phosphoinositol

Fig. 1. Chemical stmcture of phosphatidylcholine (PC) (1) and other related phosphohpids. R C O represents fatty acid residues. The choline fragment may be replaced by other moieties such as ethanolamine (2) to give phosphatidylethanolamine (PE), inositol (3) to give phosphatidylinositol (PI), serine (4), or glycerol (5). IfH replaces choline, the compound is phosphatidic acid (6). The corresponding lUPAC-lUB names ate (1), l,2-diacyl-t -glyceto(3)phosphocholine (2), l,2-diacyl-t -glyceto(3)phosphoethanolamine (3), 1,2-diacyl-t -glyceto(3)phosphoinositol (4), 1,2-diacyl-t -glyceto(3)phospho-L-serine and (5), l,2-diacyl-t -glyceto(3)phospho(3)-t -glycetol.

Phosphoinositol kinases Phosphatidylinositol kinases Phosphatidylinositide kinases... 

Mediator Receptor-hormone complex cAMP,cGMP,Ca k metabolites of complex phosphoinositols, kinase cascades... 

A second well characterized signal transduction pathway, which is subject to lithium inhibition, is the phosphoinositol cascade (see Chapter 11, in particular Figure 11.8). A number of enzymes of this pathway contain a common amino acid sequence that constitutes a lithium-sensitive Mg2+ binding site, and it has been proposed that lithium exerts some of... 

Zhao K, Wang W, Rando OJ, Xue Y, Swiderek K, Kuo A, Crabtree GR (1998) Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95 625-636... 

Some sensory neurons of the VNO express two gene superfamilies, termed Vlr and V2r, that encode over 240 proteins of the seven-transmembrane type (Matsunami and Buck, 1997). These G-protein-linked putative pheromone receptors are distantly related to the main olfactory system s receptors. Receptors of the VNO are linked to different G-proteins, and their extracellular N-terminal domains are longer than those of the receptors in the main olfactory system. (Vi receptors are linked to Gi-proteins and V2 receptors to Go-proteins). The intracellular excitation mechanism in VNO sensory neurons also differs from that in the main olfactory systems instead of linking to adenylyl cyclase, the VNO receptors activate the phosphoinositol second messenger system. This has been demonstrated in several mammalian species. In hamsters, aphrodisin increases inositol 1,4,5-trisphosphate (IP3) levels in VNO membranes. Boar seminal fluid and urine stimulate increases of IP3 in the VNO of the female pig. (However, in the pig, the VNO is not necessarily essential for responses to pheromones [Dorries etal., 1997]). 

This enzyme [EC 2.3.1.23], also called lysolecithin acyl-transferase and lysophosphatidylcholine acyltransferase, catalyzes the reaction of an acyl-CoA derivative with 1-acyl-5 n-glycero-3-phosphocholine to yield coenzyme A and l,2-diacyl-5 n-glycero-3-phosphocholine. The enzyme preferentially acts on unsaturated acyl-CoA derivatives, but l-acyl-5 n-glycero-3-phosphoinositol can also act as the acceptor. 

Non-receptor serine/threonine kinases and dual specificity kinases cAMP-dependent protein kinase (PKA) Phosphoinositol-3-kinase (PI-3K) Cyclin-dependent kinase (CDK) Mitogen-activated protein kinase (MAPK) MAPKK (ERK)... 

Because lithium affects second-messenger systems involving both activation of adenylyl cyclase and phosphoinositol turnover, it is not surprising that G proteins are also found to be affected. Several studies suggest that lithium may uncouple receptors from their G proteins indeed, two of lithium s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and thyroid-stimulating hormone (TSH) receptors from their G proteins. 

The major current working hypothesis for lithium s therapeutic mechanism of action supposes that its effects on phosphoinositol turnover, leading to an early relative reduction of myoinositol in human brain, are part of an initiating cascade of intracellular changes. Effects on specific isoforms of protein kinase C may be most relevant. Alterations of protein kinase C-mediated signaling alter gene expression and the production of proteins implicated in... 

Miyakawa, Y. Rojnuckarin, P. Habib, T. Kaushansky, K. Thrombopoietin induces phosphoinositol 3-kinase activation through SHP2, Gab, and insulin receptor substrate proteins in BAF3 cells and primary murine megakaryocytes. J. Biol. Chem., 276, 2494-2502 (2001)... 

Yotsushima, K. Mitsui, T. Hayakawa, T. Purification of phosphoinositol kinase from suspension-cultured cells of rice (Oryza sativa L.). Biosci. Biotech-nol. Biochem., 59, 1953-1955 (1995)... 

When IL-2 binds to high-affinity receptors, it becomes internalized following receptor-mediated endocytosis. After high-affinity binding, there is an increase in the stimulation of phosphoinositol turnover, redistribution of protein kinase C from the cytoplasm to the cell membrane, and an increased expression of IL-2 receptors, with low-affinity receptors being preferentially increased. 

---