Cyclic inositol 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. 

Figure 22.4 Injury to endothelial cells can lead to vasospasm. Normal endothelial cells release nitric oxide (NO) which relaxes smooth muscle this is achieved by nitric oxide increasing the concentration of cyclic GMP within smooth muscle fibres and cyclic GMP relaxing the smooth muscle. Injured endothelial cells secrete very little nitric oxide but secrete more endothelin. The latter increases the formation of inositol trisphosphate (IP3), which binds to the sarcoplasmic reticulum (SR) where it stimulates the Ca ion channel. The Ca ion channel in the plasma membrane is also activated. Both effects result in an increase in cytosolic Ca ion concentration, which then stimulates contraction (vasospasm). This reduces the diameter of the lumen of the artery.

ACPD, fra/7S-l-amino-cyclopentyl-l,3-dicarboxylate AMPA, DL-tt-amino-3-hydroxy-5-methylisoxazole-4-propionate cAMP, cyclic adenosine monophosphate CQNX, 6-cyano-7-nitroquinoxaline-2,3-dione DAG, diacylglycerol IP3, inositol trisphosphate LSD, lysergic acid diethylamide MCPG, a-methyl-4-carboxyphenylglycine. 

Gerasimenko OV, Gerasimenko JV, Tepikin AV, Petersen OH. 1995. ATP-dependent accumulation and inositol trisphosphate- or cyclic ADP-ribose-mediated release of Ca2+ from the nuclear envelope. Cell 80 439-444. 

Fig. 2 Presynaptic mGluRs on human and rat neocortical cholinergic (ACh) nerve endings and effect of the HIV-1 protein Tat. In human neocortex, Tat activates mGluRl leading to inositol trisphosphate (IP3) production, IP3 receptor (IP3R) activation, mobilization of Ca2+ from the endoplasmic reticulum (ER), and vesicular ACh release. In rat neocortex ACh terminals Tat binds to an unidentified receptor whose activation also leads to ACh release. This release again is dependent on intraterminal Ca2+, but this is mobilized by ryanodine receptor (RYR) activation via the endogenous agonist cyclic adenosine diphosphoribose (cADPR).

Lee, H. C., and Aarhus, R. (1995). A derivative of NADP mobilizes calcium stores insensitive to inositol trisphosphate and cyclic ADP-ribose. J. Biol Chem. 270,2152-2157. 

There are two major types of vasopressin receptors, VI and V2. The VI receptor occurs in vascular smooth muscle and is coupled via to activation of the phosphoinositide cascade-signaling system and generation of the second messenger inositol trisphosphate (IP3) and diacylglycerol. V2 receptors are found in kidney and are coupled via to activation of adenylate cyclase and production of the second messenger cyclic AMP. 

Little is known of the intracellular events involved in the augmentation of cyclic AMP accumulation elicited by H, -receptors in mammalian brain slices. However, it seems certain that another second messenger is involved, since the effect is not observed in membrane preparations [81, 205]. Calcium appears to be important for the response, since removal of external calcium reduces H,-receptor-mediated cyclic AMP accumulation in guinea-pig cerebral cortical slices [206]. Inositol phospholipid breakdown or its products (inositol trisphosphate and diacylglycerol) may also be involved, since H,-receptor stimulation is accompanied by an accumulation of inositol phosphates in slices of guinea-pig cerebral cortex [60, 207, 208]. Inositol trisphosphate may then... 

Supattopone, P., Danoff, S. K., Theibert, A., et al. 1988). Cyclic AMP-dependent phosphorylation of brain inositol trisphosphate receptor decreases its release of calcium. Proc. Natl. Acad. Sci. U.S.A. 85, 8747-8750. 

Second messengers are specific intracellular components that are indirectly stimulated by the first messengers to activate intracellular components such as certain enzymes termed protein kinases (PKs). The most studied second messengers are calcium ion, inositol trisphosphate (IP3), diacylglycerol (DAG), cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP). 

Europe-Finner, G.N. P.C. Newell. 1987. Cyclic AMP stimulates accumulation of inositol trisphosphate in Dictyostelium. J. Cell Sci. 87 221-9. 

A further intriguing aspect of the biological chemistry of cyclic inositol phosphates lies in the fact that they are not only detected as products of hydrolysis of PIPj catalysed by phospholipase C, but they may also be intermediates in this enzyme-catalysed reaction. The water-soluble products of the breakdown of PIPj catalysed by phospholipase C were hydrolysed in 0-labelled water in the presence of acid (Wilson et al., 1985a,b). The resulting trisphosphates after work-up were analysed by mass spectrometry-gas chromatography. Since only reactive cyclic phosphates are hydrolysed (with label incorporation) in dilute acid, Majerus and coworkers were able to use this technique to quantify the initial cyclic phosphate product of the phospholipase C reaction. Similar experiments were performed with phosphatidyl inositol 4-monophosphate (PIP) and phosphatidyl inositol (PI) as substrates and the results confirmed by hplc ananlysis. 

For the two types of phospholipase C (PLC) enzyme studied, the proportion of cyclic phosphate, as a percentage of the total phosphate product, ranges from zero to 73%. PLC-I-catalysed hydrolysis of PI yields cyclic inositol (1 2) monophosphate as 63-73% of the isolated phosphate product. However, the amount of observed cyclic product consistently decreases with increased phosphorylation of the substrate. The important conversion of PIPj to the biologically active trisphosphate IP(1,4,5)3 yields only 0-15% of CIP3 as product. 

Fig. 4.12. Second messenger mechanisms for cyclic adenosine monophosphate (cAMP) and inositol trisphosphate. (From Simon JB, Golan DE, Tashjian A, Armstrong E, et al., eds. Chapter 1, Drug-Receptor Interactions. In Principles of Pharmacology The Pathophysiologic Basis of Drug Therapy. Baltimore Lippincott Williams Wilkins, 2004, pp. 3-16, with permission.)...

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