Inositol 1,4.5-trisphosphate

The GABAB-receptors, the muscarinic M2- and IVU-receptors for acetylcholine, the dopamine D2-, D3-and D4-receptors, the a2-adrenoceptors for noradrenaline, the 5-HTiA F-receptors for serotonin, and the opioid p-, 8- and K-receptors couple to G proteins of the Gi/o family and thereby lower [1] the cytoplasmic level of the second messenger cyclic AMP and [2] the open probability ofN- andP/Q-type Ca2+ channels (Table 1). The muscarinic Mr, M3- and M5-receptors for acetylcholine and the ai-adrenoceptors for noradrenaline couple to G proteins of the Gq/11 family and thereby increase the cytoplasmic levels of the second messengers inositol trisphosphate and diacylglycerol (Table 1). The dopamine Dr and D5-receptors and the (3-adrenoceptors for noradrenaline, finally, couple to Gs and thereby increase the cytoplasmic level of cyclic AMP. 

Inositol trisphosphate Receptor/G-protein cascades. As discussed above, IP3 is one of the products of the hydrolysis of PIP2. To say that it acts as a second messenger means that a rise in its concentration occurs as a result of some meaningful event and that the rise causes some other significant event. In terms of information flow, the signal immediately preceding the rise in IP3 is a rise in the concentration of active PLC. This rise is due to the binding of a subset of G-proteins... 

The inositol is present in ph osphatidylinositol as the stereoisomer, myoinositol (Figure 14—8). Phosphatidylinositol 4,5-hisphosphate is an important constituent of cell membrane phosphohpids upon stimulation by a suitable hormone agonist, it is cleaved into diacylglycerol and inositol trisphosphate, both of which act as internal signals or second messengers. 

Figure 43-7. Phospholipase C cleaves PIPj into diacylglycerol and inositol trisphosphate. R, generally is stearate, and Rj is usually arachido-nate. IP3 can be dephosphorylated (to the inactive I-1,4-P2) or phosphorylated (to the potentially active I-1,3,4,5-P4).

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.

I Kojima, H Shibata, E Ogata. (1986). Pertussis toxin blocks angiotensin II-induced calcium influx but not inositol trisphosphate production in adrenal glomerulosa cell. FEBS Lett 204 347-351. 

The other activity associated with transmembrane receptors is phospholipase C. Phosphatidyl inositol is a membrane phospholipid that after phosphorylation on the head group is found in the membrane as a phos-photidylinostitol bis phosphate. Phospholipase C cleaves this into a membrane associated diacylglycerol (the lipid part) and inositol trisphosphate (IP3, the soluble part). Both play a later role in elevating the level of the second messenger, Ca2+. 

Bultynck, G Sienaert, I., Parys, J. B. etal. Pharmacology of inositol trisphosphate receptors. Pflugers Arch. 445 629-642, 2003. 

Yang, J., McBride, S., Mak, D. O. etal. Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca(2+) release channels. Proc. Natl Acad. Sci. U.S.A. 99 7711-7716, 2002. 

IP3, inositol trisphosphate DARPP-32, dopamine and cAMP-regulated phosphoprotein of 32kDa RIM, Rab3a interacting molecule ... 

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). 

Rosel, P, Arranz, B., San, L. et al. Altered 5-HT2A binding sites and second messenger inositol trisphosphate (IP3) levels in hippocampus but not in frontal cortex from depressed suicide victims. Psych. Res. Neuroimag. 99 173-181,2000. 

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Swatton JE, Morris SA, Cardy TJA, Taylor CW 1999 Type 3 inositol trisphosphate receptors in RINm5F cells are biphasically regulated by cytosolic Ca2+ and mediate quantal Ca2+ mobilization. Biochem j 344 55—60... 

Bulbring E, T omita T 1969 Effect of calcium, barium and manganese on the action of adrenaline in the smooth muscle of the guinea-pig taenia coli. Proc R Soc Lond B Biol Sci 172 121-136 Marchant JS, Taylor CW 1998 Rapid activation and partial inactivation of inositol trisphosphate receptors by inositol trisphosphate. Biochemistry 37 11524-11533 Somlyo AV, Horiuti K, Trentham DR, Kitazawa T, Somlyo AP 1992 Kinetics of Ca2+ release and contraction induced by photolysis of caged D-myo-inositol 1,4,5-trisphosphate in smooth muscle the effects of heparin, procaine, and adenine nucleotides. J Biol Chem 267 22316-22322... 

Chadwick CC, Saito A, Fleischer S 1990 Isolation and characterization of the inositol trisphosphate receptor from smooth muscle. Proc Nad Acad Sci USA 87 2132-2136 Chambers P, Neal DE, Gillespie JI1999 Ryanodine receptors in human bladder smooth muscle. 

Somlyo AP, Somlyo AV 2000 Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol 522 177—185 Somlyo AP, Devine CE, Somlyo AV, N orth SR 1971 Sarcoplasmicreticulumand the temperature-dependent contraction of smooth muscle in calcium-free solutions. J Cell Biol 51 722—741 Somlyo AP, Walker JW, Goldman YE et al 1988 Inositol trisphosphate, calcium and muscle contraction. Philos Trans R Soc Lond B Biol Sci 320 399 114 Somlyo AP, Wu X, Walker LA, Somlyo AV 1999 Pharmacomechanical coupling the role of calcium, G-proteins, kinases and phosphatases. Rev Physiol Biochem Pharmacol 134 201-234... 

Francesconi, A. and Duvoisin, R. (2000) Opposing effects of protein kinase C and protein kinase A on metabotropic glutamate receptor signaling selective desensitization of the inositol trisphosphate/Ca2+ pathway by phosphorylation of the receptor-G protein-coupling domain. Proc. Natl. Acad. Sci. USA 97,6185-6190. 

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