Inositol 1,4,5-trisphosphate receptor phosphorylation

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. 

Joseph, S.K. and Ryan, S.V. (1993) Phosphorylation of the inositol trisphosphate receptor in isolated rat hepatocytes. Journal of Biological Chemistry, 258 23059-23065. 

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+. 

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). 

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. 

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.

Inositol trisphosphate, a water-soluble compound, diffuses from the plasma membrane to the endoplasmic reticulum, where it binds to specific IP3 receptors and causes Ca2+ channels within the ER to open. Sequestered Ca2+ is thus released into the cytosol (step (5)), and the cytosolic [Ca2+] rises sharply to about 10 6 m. One effect of elevated [Ca2+] is the activation of protein kinase C (PKC). Diacylglycerol cooperates with Ca2+ in activating PKC, thus also acting as a second messenger (step (6)). PKC phosphorylates Ser or Thr residues of specific target proteins, changing their catalytic activities (step (7)). There are a number of isozymes of PKC, each with a characteristic tissue distribution, target protein specificity, and role. 

Hanbauer I, Wink D, Osawa Y, Edelman GM, Gaily JA (1992) Role of nitric oxide in NMDA-evoked release of [3H]-dopamine from striatal slices. Neuroreport 3 409-12 Hartell NA (1994) cGMP acts within cerebellar Purkinje cells to produce long term depression via mechanisms involving PKC and PKG. Neuroreport 5 833-6 Haug LS, Jensen V, Hvalby O, Walaas SI, Ostvold AC (1999) Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic nucleotide-dependent kinases in vitro and in rat cerebellar slices in situ. J Biol Chem 274 7467-73... 

Wagner LE, 2nd, Li WH, Yule DI (2003) Phosphorylation of type-1 inositol 1,4,5-trisphosphate receptors by cyclic nucleotide-dependent protein kinases a mutational analysis of the functionally important sites in the S2+ and S2- splice variants. J Biol Chem 278 45811-7 Wall ME, Francis SH, Corbin JD, Grimes K, Richie-Jannetta R, Kotera J, Macdonald BA, et al. (2003) Mechanisms associated with cGMP binding and activation of cGMP-dependent protein kinase. Proc Natl Acad Sd USA 100 2380-5... 

The opposing effects on smooth muscle (A) of a- and p-adrenoceptor activation are due to differences in signal transduction, ai -Receptor stimulation leads to intracellular release of Ca2+ via activation of the inositol trisphosphate (IP3) pathway. In concert with the protein calmodulin, Ca2+ can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin (— vasoconstriction). 012-Adrenoceptors can also elicit a contraction of smooth muscle cells by activating phospholipase C (PLC) via the py-subunits of G, proteins. 

As shown in Figure 14.6, a proportion of the phosphatidylinositol in membranes undergoes two successive phosphorylations to yield phosphatidylinositol bisphosphate. This is a substrate for hormone-sensitive phospholipase C, which is activated by the G-protein-GTP complex released into the cell membrane by a hormone receptor following binding of the hormone at the outer surface of the membrane. Phospholipase C hydrolyzes phosphatidylinositol bisphosphate to release diacylglycerol and inositol trisphosphate. 

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].

Komalavilas, P., and Lincoln, T. M. (1994). Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase. ]. Biol. Chem. 269, 8701-8707. 

Danoff, S.K., Ferris, C.D., Donath, C., Fischer, G.A., Munemitsu, S., Ullrich, A., Snyder, S.H., and Ross, C.A. (1991) Inositol 1,4,5-trisphosphate receptors distinct neuronal and nonneuronal forms derived by alternative splicing differ in phosphorylation. Proceedings of the National Academy of Sciences of the United States of America, 88 2951-2955. 

Nakade, S., Rhee, S.K., Hamanaka, H., and Mikoshiba, K. (1994) Cyclic AMP-dependent phosphorylation of an immunoaffinity-purified homotetrameric inositol 1,4,5-trisphosphate receptor (type I) increases Ca flux in reconstituted lipid vesicles. Journal of Biological Chemistry, 269 6735-6742. 

Vanderheyden V, Wakai T, Bultynck G, De Smedt H, Parys JB, Fissore RA. 2009. Regulation of inositol 1,4,5-trisphosphate receptor type 1 function during oocyte maturation by MPM-2 phosphorylation. Cell Calcium 46(1) 56-64. 

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

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