The phosphoinositide cycle

The formation of inositol phosphates, including inositol 1,4,5-trisphosphate (IP3) has been demonstrated in ovarian cells [13,14], The levels of these compounds are raised for periods of seconds to minutes after addition of LH to isolated cells. However, these LH-induced changes are an order of magnitude smaller than the changes in cyclic AMP. The transient and small effects of LH on polyphosphoinositide turnover has made it difficult to establish accurate kinetics and dose response charac- 

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H, receptors also can stimulate the activity of phospholipase A2 (PLA2), with the subsequent release of arachido-nate and its metabolites. In platelets, this response does not require activation of the phosphoinositide cycle and is inhibited by pertussis toxin, suggesting a second, distinct Gj/o-protein-mediated transduction mechanism. In cells transfected with the H, receptor, PLA2 activation is partially inhibited by pertussis toxin, also suggesting at least two transduction systems [30,34],... 

The profound effects of Li+ upon phosphoinositide metabolism and cell signaling have been the subject of several recent reviews [54,81,85,86]. These effects are dependent upon receptor stimulation of the phosphoinositide cycle by a range of stimuli, including norepinephrine, serotonin, and carbachol the basal turnover of this cycle is largely unaffected by Li+ [82,87,88]. 

Whatever the therapeutic mechanism of action of Li+ is, the facts are that Li+ does indeed inhibit the turnover of the phosphoinositide cycle and does alter the levels of both second messengers, Ins(l,4,5)P3 and DAG, either or both of which may have wide-reaching secondary effects. 

We have recently shown [1] that phosphatidylinositol (PI) was synthesized mainly (or perhaps exclusively) in the endoplasmic reticulum and subsequently transferred to the plasma membrane of cells to allow the phosphoinositide cycle of signal transduction to proceed we have also shown that there is nearly the same quantitative distributions of PI molecular species in plasma membranes on one side and microsomes on the other side. In both membrane preparations [2, 3] the molecular species 16 0/18 2 was largely predominant (75-80 mol%). All other molecular species (16 0/18 3,18 2/18 2,18 1/18 2, 16 0/18 1, 18 0/18 2) presented percentages lower than 8%. However the question remained do the Pl-lanase and phosphatidylinositolphosphate (Plp)-kinase, which initiate the phosphoinositide cycle in plasma membranes, discriminate between the PI molecular species ... 

Does the Action of LP on the Phosphoinositide Labeling Cycle Explain the... 

The increase in phosphoinositide hydrolysis appears to occur during the G0 and early G[ phases of the cell cycle. Cells will not tolerate a sustained increase in intracellular Ca2+ and actively extrude the ion. Recent evidence in B lymphocytes, using calcium probes and image intensifies, shows that when surface immunoglobulin is crosslinked the rise of intracellular Ca2+ occurs in repeated short bursts [37]. 

S ATP + l-stearoyl-2-arachidonoyl-sn-glycerol <5> (<5>, since diacylglycerol kinase is an enzyme of the phosphatidylinositol cycle, its natural substrate could be l-stearoyl-2-arachidonoyl-sn-glycerol, thought to be the main diacylglycerol analog generated from phosphoinositide [7]) (Reversibility <5> [7]) [7]... 

Burke L et al (2005) Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma. Clin Cancer Res 11 232-241 Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296 1655-1657... 

Fig. 2. Messengers mediating the initial and sustained phases of the All-induced cellular response. Initial phase All-elicited hydrolysis of PIP2 induces a transient rise in cytosolic calcium (via IP3), a transient activation of calcium-, calmodulin-dependent protein kinases, a transient increase in the phosphorylation of early-phase phosphoproteins (Pra-P), and a transient cellular response. Sustained response All-elicited hydrolysis of phosphoinositides generates a sustained increase in the diacylglycerol (DG) content of the plasma membrane. In conjunction with a sustained increase in plasma membrane calcium cycling, DG induces the sustained activation of protein kinase C (CK), the sustained increase in the phosphorylation of late-phase phosphoproteins (P -P) and the sustained cellular response.

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