Inositol 1,4,5-trisphosphate inhibition

Cifuentes, M.E., Delaney, T., and Rebecchi, M.J., 1994, D-rayo-Inositol 1,4,5-trisphosphate inhibits binding of phospholipase C-delta 1 to bilayer membranes. J. Biol. Chem. 269 1945-1948. 

Fig. 12. Tentative model of the signal transduction chain that links the perception of pectic fragments to defense responses in carrot cells. Abbreviations apy, heterotrimeric G protein CaM, calmodulin 4CL, 4-coumarate-CoA ligase CTX, cholera toxin FC, fusicoccine GDP-P-S and GTP-y-S, guanosine 5 -0-(2-thiodiphosphate) and guanosine 5 -0-(3-thiotriphosphate) IP3, 1,4,5-inositol trisphosphate PAL, phenylalanine ammonia-lyase PLC, phospholipase C PR, pathogenesis related PTX, pertussis toxin Rc, receptor SP, staurosporine. Activation and inhibition are symbolized by + and -respectively.

This can be illustrated by known interactions between the cAMP and Ca2+ pathways. A first messenger that initially activates the cAMP pathway would be expected to exert secondary effects on the Ca2+ pathway at many levels via phosphorylation by PKA. First, Ca2+ channels and the inositol trisphosphate (IP3) receptor will be phosphorylated by PKA to modulate intracellular concentrations of Ca2+. Second, phospholipase C (PLC) is a substrate for PKA, and its phosphorylation modulates intracellular calcium concentrations, via the generation of IP3) as well as the activity of PKC, via the generation of DAG, and several types of CAMK. Similarly, the Ca2+ pathway exerts potent effects on the cAMP pathway, for example, by activating or inhibiting the various forms of adenylyl cyclase expressed in mammalian tissues (see Ch. 21). 

Mak D-O, McBride S, Foskett JK 1998 Inositol 1,4,5-trisphosphate activation of inositol trisphosphate receptor Ca2+ channel by ligand tuning of Ca2+ inhibition. Proc Natl Acad Sci USA 95 15821-15825... 

Figure 11.21 Outline of synthesis of phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine. Note in the synthesis of phosphatidylinositol, the free base, inositol, is used directly. Inositol is produced in the phosphatase reactions that hydrolyse and inactivate the messenger molecule, inositol trisphosphate (IP3). This pathway recycles inositol, so that it is unlikely to be limiting for the formation of phosphatidylinositol bisphosphate (PIP )- This is important since inhibition of recycling is used to treat bipolar disease (mania) (Chapter 12, Figure 12.9). Full details of the pathway are presented in Appendix 11.5. Inositol, along with choline, is classified as a possible vitamin (Table 15.3).

Fig. 1. Major signaling linkages of the subfamilies of G protein-coupled 5-HT receptors are shown. Stimulation is indicated by an arrow overlayed with a + sign. Inhibition is indicated by an arrow overlayed with a sign. Abbreviations AC, adeny-lyl cyclase MEK, mitogen and extracellular signal regulated kinase ERK, extracellular signal regulated kinase PKC, protein kinase C DAG, diacylglycerol IP3, inositol trisphosphate.

Further studies have revealed that pumiliotoxin B interacts with voltage-dependent sodium channels to elicit an increased influx of sodium ions (101,102) and, in brain and heart preparations, a stimulation of phosphoino-sitide breakdown (101,103-106). The phosphoinositide breakdown can, via inositol trisphosphate, cause release of calcium from internal storage sites. The cardiotonic activity of pumiliotoxin B and various congeners and synthetic analogs correlates well with the stimulation of phosphoinositide breakdown (104,105). A number of studies on stimulation of sodium uptake by pumiliotoxin B and inhibition by local anesthetics and other agents have appeared (106-108). The effects of pumiliotoxin B on neuromuscular preparations have been reinterpreted as due primarily to effects on sodium channels, although additional direct effects on calcium mobilization remain possible (109). It has recently been proposed that pumiliotoxin B enhances the rate of activation of sodium channels (110). One characteristic effect of pumiliotoxin B is to elicit repetitive firing in neurons, apparently because of effects on sodium channel function (109-111). 

In osteoblasts, keratinocytes, and colonocytes, andpossibly other cells, calcitriol acts via cell surface receptors linked to phospholipase C, resulting in release of diacylglycerol and inositol trisphosphate (Section 14.4.1), followed by opening of intracellular calcium channels and activation of protein kinase C and mitogen-activated protein (MAP) kinases. The effect of this is inhibition of cell proliferation and induction of differentiation. A variety of analogs of calcitriol that do not bind to the nuclear receptor do bind to, and activate, the cell surface receptor, including l,25-dihydroxy-7-dehydrocholesterol and 1,25-dihydroxylumisterol. The rapid nongenomic responses to vitamin D can be demonstrated in knockout mice that lack the vitamin D nuclear receptor (Farach-Carson and Ridall, 1998 Nemere and Farach-Carson, 1998). 

Figure 2.13. Histamine H,-receptor-mediated inositol phospholipid hydrolysis. Stimulation of H,-receptors leads to activation of a phospholipase C. probably via a guanine-nucleotide regulatory protein (N). which catalyses the hydrolysis of phosphatidylinositol 4.5 -bisphosphate (PIP2) to give inositol trisphosphate (IP3) and 1,2-diacylglycerol (DG). IP3 is then broken down by phosphatases to eventually yield free myo-inositol. Lithium ions can inhibit the conversion of inositol 1-phosphate (IP,) to myo-inositol. Free inositol then interacts with CDP-diacylglycerol,formed by a reaction between phosphatidic acid (PA) and CTP, to yield phosphatidylinositol (PI). Phosphorylation of PI by kinases completes the lipid cycle by reforming PIP2. Modified from [147,148].

B. Mechanism of Action The mechanism of action of lithium is not well defined. The drug inhibits the recycling of neuronal membrane phosphoinositides involved in the generation of inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers are important in amine neurotransmission, including that mediated by central adrenoceptors and muscarinic receptors (Figure 29-2). 

Zholos, A.V., S. Komori, H. Ohashi T.B. Bolton. 1994. C f inhibition of inositol trisphosphate-induced Ca release in single smooth muscle cells of guinea-pig small intestine. J. Physiol. 481.1 97-109. 

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