Phosphoinositide turnover

Ashkenazi, A., Winslow, J. W., Peralta, E. G. etal. An M2 muscarinic receptor subtype coupled to both adenylyl cyclase and phosphoinositide turnover. Science 238 672-675,1987. 

In contrast to their more highly expressed counterparts, the 3-phosphoinositides do not serve as substrates for phospholipase C (PLC), the enzyme known to be activated in stimulated phosphoinositide turnover. This observation indicates that the 3-phosphoinositides themselves, rather than their breakdown products, are likely to... 

A single enzyme, inositol monophosphatase, leads to loss of the remaining phosphate and the regeneration of free inositol. This enzyme exhibits similar affinities for all five of the equatorial inositol monophosphate hydroxyls. Inositol 2-phosphate, which is not produced in this degra-dative pathway, is a poor substrate, a property that is probably attributable to its axial configuration. The enzyme is inhibited by Li+ in an uncompetitive manner i.e. the degree of inhibition is a function of substrate concentration. The putative link between the ability of Li+ to interfere with phosphoinositide turnover and its therapeutic efficacy in the treatment of bipolar disorders is discussed in Box 20-1 and Chapter 55. It should be noted that unlike most other tissues, brain can synthesize inositol de novo by the action of inositol monophosphate synthase, which cyclizes glucose 6-phosphate to form I(3)P. The enzyme has been localized immunohistochemically to the brain vasculature. 

The action of Li+ on inositol monophosphatase has greatly facilitated the use of [3H] inositol in the study of stimulated phosphoinositide turnover [19]. Berridge and colleagues demonstrated that in the presence of both Li+ and a phosphoinositide-linked ligand, the amount of labeled intracellular inositol phosphates that accumulates... 

Efferth T, Volm M (1992) Expression of protein kinase C in human renal cell cardnoma cells with inherent resistance to doxorubicin. Anticancer Res 12 2209-2211 Eguchi Y, Srinivasan A, Tomaselli KJ, Shimizu S, Tsujimoto Y (1999) ATP-dependent steps in apoptotic signal transduction. Cancer Res 59 2174-2181 Ek TP, Campbell MD, Deth RC, Gowraganahalli J (1989) Reduction of norepinephrine-induced tonic contraction and phosphoinositide turnover in arteries of spontaneously hypertensive rats. A possible role for protein kinase C. Am J Hy-pertens 2 40-45... 

Manna s data (1991) of the efficacy of a nimodipine and lithium combination are of particular interest in reference to the above hypotheses related to combined effects on calcium-related mechanisms. Lithium obviously exerts complex effects on a variety of systems in brain, but its effects on phosphoinositide turnover and cyclic adenosine monophosphate and downstream effects on 1,4,5-inositol triphosphate (IP3) metabolism in calcium-related processes (as reviewed by Berridge 1989 H. L. Meltzer 1990 and... 

Post et al. 1992) are also worthy of consideration. Effects on the IP3 receptor-mediated calcium release have also been shown to affect ultrarapid neuronal and cellular calcium oscillations in several different types of preparations, raising the possibility that IP3 modulation, either directly or indirectly through effects on phosphoinositide turnover, could be important to some elements of lithium s and related agents mood-stabilizing effects (Berridge 1989 Dixon et al. 1992 Lupu-Meiri et al. 1994 Varney et al. 

The second-messenger linkage of postsynaptic 5-HTj receptors has been connected in various neurons with either inhibition of adenylate cyclase, stimulation of adenylate cyclase, or inhibition of phosphoinositide turnover (Harrington et al. 1992]. 

Cherifi, Y., Pigeon, C., Le Romancer, M., Bado, A., Reyl-Desmars, F., Lewin, M.J.M., 1992. Purification of a histamine H3 receptor negatively coupled to phosphoinositide turnover in the human gastric cell line HGT1. J. Biol. Chem. 267, 25315-25320. 

Nicolle M. M., Colombo P. J., Gallagher M., and McKinney M. (1999). Metabotropic glutamate receptor-mediated hippocampal phosphoinositide turnover is blunted in spatial learning-impaired aged rats. J. Neurosci. 19 9604-9610. 

Balduini W, Cimino M, Reno F, Marini P, Princivalle A, Cattabeni F. Effects of postnatal or adult chronic acetylcholinesterase inhibition on muscarinic receptors, phosphoinositide turnover and ml mRNA expression. Eur J Pharm 1993 248 281-288. 

Huque, T. and Bruch, R. C., Odorant- and guanine nucleotide-stimulated phosphoinositide turnover in olfactory cilia, Biochem. Biophys. Res. Commun., 137, 36, 1986. 

Very recent efforts to further evaluate the functional implications of phosphoinositol signaling in vertebrate chemosensory transduction have led to the discovery that not only the phosphoinositol breakdown pathway catalyzed by phospholipase C, but also membrane phosphoinositols themselves involving phosphoinositide-3-kinase may play a functional role in the transduction process. It was found that 3-phosphoinositides signaling in concert with the canonical phosphoinositide turnover pathway modulate the cyclic nucleotide signaling cascade downstream of the receptor. The data suggest that 3-phosphoinositide, the primary product of PI3K activity, attenuates the cyclic nucleotide-dependent excitation of olfactory neurons (Spehr et al., 2002). 

Measurement of Phosphoinositide Turnover. As a result of these labeling experiments, two analytical procedures can be used to assess the involvement of the phosphoinositides in stimulus-induced activation of platelets by the agonist, PAF. One uses the measurement of the change in phosphoinositide levels per se as determined by [32P]phosphate labeling, and the other uses an assay to determine the accumulation of [3H]inositol phosphates through myo-[3H]inositol labeling. 

Like the D2 receptor (see further, Section 11.1), the Dj receptor belongs to the family of G protein-coupled receptors and is characterized by its stimulatory activity on adenylyl cyclase being coupled to either G0 or Gs protein (Spano et ah, 1978 Kebabian and Caine, 1979 Herve et ah, 1993). Biochemical and electrophysiological studies have also evidenced a Di-like receptor coupled to stimulation of phosphoinositide turnover (Missale et ah, 1998 Niznik et ah, 2003). 

In animal systems, it is well documented that phosphoinositides and inositol phosphates participate in various signal transduction processes. One of the most studied signaling events involved in phosphoinositide turnover is the generation... 

Xu C, Watras J, Loew LM. Kinetic analysis of receptor-activated phosphoinositide turnover. J. Cell Biol. 2003 161 779-791. 

For the past two decades Dr. Shivendra D. Shukla s major interest has been phosphoinositide turnover, platelet activating fector receptor signaling and platelet pharmacology. He has made original contributions in this field. His research has been supported by American Heart Association, National Institute of Health and NIH Research Career Development Award. 

Shukla SD, Thurston AW, Zhu CY, Dhar A. Platelet activating factor receptor functions via phosphoinositide turnover and tyrosine kinase in Platelet activating factor recqrtor Signal mechanisms and molecular biology. Edited by S. D. Shukla, CRC Press 1993 41-59... 

Stilbenoids from the roots of Vitis thunbergii displayed strong antiplatelet activity, such as (-)-viniferal (771), ampelopsin C, miyabenol A and (+)-vitisin C (700) [245]. Marchantinquinone exerted antiplatelet effects by inhibiting phosphoinositide turnover [514]. Antiplatelet aggregation activities have also been reported for piceid [390,515], rhaponticin [515] gigantol, moscatilin, scoparone and scopoletin [92]. 

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