Inositol trisphosphate formation

Boekhoff I., Raming K. and Breer H. (1990b) Pheromone-induced stimulation of inositol-trisphosphate formation in insect antennae is mediated by G-proteins. J. Comp. Physiol. B 160, 99-103. 

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).

Figure 12.5 Effector mechanism activation of a membrane-bound phospholipase. An example is activation of a membrane-bound phospholipase which hydrolyses phosphatidylinositol bisphosphate (PIP2) and results in the formation of the two messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). Messenger IP3 binds to a receptor on the endoplasmic reticulum that results in release of Ca ions into the cytosol. DAG, which remains within the membrane, activates protein kinase-C at the membrane surface. When the kinase leaves the membrane, it is unclear how it remains active or loss of activity is prevented, so that it can phosphorylate proteins in the cytosol or even the nucleus. An example is adrenaline binding to the a-receptor in the liver, in which Ca ions stimulate glycogenolysis.

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.

Three subtypes of vasopressin G protein-coupled receptors have been identified. Via receptors mediate the vasoconstrictor action of vasopressin V , receptors potentiate the release of ACTH by pituitary corticotropes and V 2 receptors mediate the antidiuretic action. Via effects are mediated by activation of phospholipase C, formation of inositol trisphosphate, and increased intracellular calcium concentration. V2 effects are mediated by activation of adenylyl cyclase. 

The signal transduction mechanisms triggered by binding of ET-1 to its vascular receptors include stimulation of phospholipase C, formation of inositol trisphosphate, and release of calcium from the endoplasmic reticulum, which results in vasoconstriction. Conversely, stimulation of PGI2 and nitric oxide synthesis results in decreased intracellular calcium concentration and vasodilation. 

The effects of VIP are mediated by G protein-coupled receptors two subtypes, VPAC1 and VPAC2, have been cloned from human tissues. Both subtypes are widely distributed in the central nervous system and in the heart, blood vessels, and other tissues. VIP has a high affinity for both receptor subtypes. Binding of VIP to its receptors results in activation of adenylyl cyclase and formation of cAMP, which is responsible for the vasodilation and many other effects of the peptide. Other actions may be mediated by inositol trisphosphate synthesis and calcium mobilization. 

Two pathways from the activated receptor are shown. At the left is activation of phospholipase Cy and formation, at a membrane-bound site, of inositol trisphosphate and diacylglycerol (DAG). The main pathway, in the center, activates Ras with the aid of the G protein Sos. Activated Ras, in turn, activates Raf and successive components of the MAPK cascade. At the right a seven-helix receptor activates both phospholipase C(3 and Ras via interaction with a (3y subunit. (B) A generalized scheme for the MAP kinase pathway. See Seger and Krebs.380... 

Van Dijken, P., Bergsma, J.C. and Van Haastert, P.J.M., 1997, Phospholipase C-independent inositol 1,4,5-trisphosphate formation in Dictyostelium cells. Activation of a plasma-membrane-bound phosphatase by receptor-stimulated Ca2+ influx. Eur. J. Biochem. 244 113-119. 

Smolenska-Sym, G., and Kacperska, A., 1996, Inositol 1,4,5-trisphosphate formation in leaves of water oilseed rape plants in response to freezing, tissue water potential and abscisic acid. Physiol. Plant 96 692-698. 

Retinoids in Transmembrane Signaling Neutrophils treated with physiological concentrations of all-tra s-retinoic acid show a dose-dependent increase in synthesis of superoxide. Inhibitor studies suggest that retinoic acid acts via an inositol trisphosphate cascade rather than calcium and protein kinase C (Koga et al., 1997). There is also evidence that all-rrans-retinoic acid leads to increased formation of cADP-ribose and nicotinic acid adenine dinucleotide phosphate as second messengers (Section 8.4.4 Dousa et al., 1996 Mehta and Cheema, 1999). 

Figure 14.6. Formation of inositol trisphosphate and diacylglycerol. Phosphatidylinos-itol kinase, EC 2.7.1.67 and hormone-sensitive phospholipase, EC 3.1.4.3.

Phospholipase C/inositol trisphosphate (IPsl/diacylglycerol (DAG). Activation of this system results in the formation of two intracellular messengers (IP3 and DAG). IP3 increases free calcium (Ca ) thus activating various enzymes. DAG activates protein kinase C, which in turn regulates various cellular functions (Fig. 1.5). 

We will examine the mechanisms and metabolic effects of hormones. Hormones can either work at the membrane or enter the cell for their functions. Three mechanisms are primary for hormones acting at the membrane, which require a transduction of the message into the cell. These transductions include (1) formation of cAMP, (2) formation of inositol trisphosphate and diacylglycerol, and (3) direct covalent modifications. The hormones that enter the cell have their effects in the nucleus. To show the physiological effects of the hormones and review the integration of carbohydrate and lipid metabolism, these hormones are examined in detail. The effects we examine include not only metabolism and its control, but the roles of individual tissues. 

Fig. 10. Crystal structure of phosphatidylinositol-PLC5 showing the C2 and catalytic domains. The position of the PH domain that would be attached to the EF-hand domain is indicated. The membrane surface would be parallel to the top surface of the molecule as shown. Calcium ions are shown hound to the active site and to the C2 domain. The position of inositol trisphosphate in space-filling format at the active site is indicated. Adapted from L.-O. Essen (1996) and Ref [32]. (See color plate section, plate no. 10.)...

Rooney, T.A., D.C. Renard, E.J. Sass A.P. Thomas. 1991. Oscillatory cytosolic calcium waves independent of stimulated inositol 1,4,5-trisphosphate formation in hepatocytes. J. Biol. Chem. 266 12272-82. 

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