Endoplasmic reticulum inositol phosphate

In summary, the release of nenrotransmitter from a presynaptic neurone into a synaptic cleft occurs via the process of exocytosis, which is regulated by the increase in Ca " ion concentration in the presynaptic terminal. The increase in Ca " ion concentration is achieved by release of Ca " ions by opening of the Ca ion channel in the endoplasmic reticulum, which is controlled by the concentration of IP3. Failure to release inositol from the inositol phosphates reduces the free inositol concentration, which interferes in the synthesis of PIP2. The phospholipase no longer catalyses a zero order reaction. Consequently, sufficient IP3 to activate the ion channel is released in the presynaptic neurone, so that less nenrotransmitter is released into the synaptic cleft (Figure 12.19). 

Phospholipase C hydrolyzes the bond between glycerol and phosphate in phosphatidylinositol 4,5-bisphos-phate, releasing two products inositol 1,4,5-trisphos-phate (IP3), which is water-soluble, and diacylglycerol, which remains associated with the plasma membrane. IP3 triggers release of Ca2+ from the endoplasmic reticulum, and the combination of diacylglycerol and elevated cytosolic Ca2+ activates the enzyme protein kinase C. 

The following effects take place because the receptors are coupled to adenylyl cyclase or to phospholipase C. Adenylyl cydase catalyzes the synthesis of cAMP, while phospholipase C catalyzes the hydrolysis of the phosphahdy -4,5-bisphos-phate, releasing inositol-1,4,5-trisphosphate (11 3). This IP3, in turn, travels to the endoplasmic reticulum, where it provokes the momentary release of calcium ions. The increase in ion levels, in turn, provokes activation of a number of protein kinases, as discussed in the Calcium and Phosphate seebon. All of these receptors are p(dypeptides that weave seven times in or out of the plasma membrane. All of these receptors are directly linked to G protein, and require G protein for transmitting their message within the membrane to various enzymes. 

The transduction of many hormonal and neuronal signals occurs through receptor-mediated activation of phosphoinositidase C (phospholipase C). This enzyme hydrolyzes phosphatidylinositol 4,5-bis-(phosphate) (PIP2) into 1,2-diacylglycerol and n-inositol 1,4,5-tris-(phosphate) in the plasma membrane. Both products are second messengers that, respectively, stimulate protein kinase C and release calcium from intracellular stores located in the endoplasmic reticulum (100). D-Inositol l,4,5-tris(phosphate) is converted via intermediary compounds to myoinositol. In return this is converted to phosphatidylinositol, which is used to replenish PIP2. 

Other drugs affect intracellular calcium channels of the endoplasmic or sarcoplasmic reticulum, e.g. inositol triphosphate receptor channels open in response to InsPs itself and certain other inositol phosphates, are sensitized by thiomersal (which increases the sensitivity of the receptor to InsPs by acting as a sulphydryl reagent) and antagonized by heparin. The various ryanodine receptor channels, at which a putative natural agonist is cyclic adenosine diphosphate ribose (cADP-R), are activated by caffeine and low concentrations of ryanodine (but antagonized by high concentrations of ryanodine and ruthenium red). 

Fig. 1. Stimulus-induced turnover of phosphatidylinositol 4,5-bisphosphate (PIPo) and the role of turnover products in signal transduction. PI, phosphatidylinositol PIP, phosphatidylinositol 4-phosphate PIPo, phosphatidylinositol 4,5 bisphosphate IP, inositol trisphosphate IP, inositol tetrakisphosphate IPo inositol bisphosphate IP, inositol monophosphate ER, endoplasmic reticulum DG, diacylglycerol MG, monoglyceride AA, arachidonic acid PA, phosphatidic acid. [Adapted from 38]...

Figure 2. The so-called canonical phosphoinositide pathway . The continuous phosphorylation/dephosphorylation reactions allow a steady-state level of Ptdins, PtdIns(4)P and PtdIns(4,5)P2 in the plasma membrane (PM). Cleavage of PtdIns(4,5)P2 by phospholipase C (PLC) generates the two well-known second messengers, inositol 1,4,5-trisphosphate (Ins(l,4,5)P3) and diacylglycerol (DAG). Besides its role as a protein kinase C (PKC) activator, DAG can be phosphorylated to phosphatidic acid (PA). The resynthesis of Ptdins from inositol and PA occurs mainly in the endoplasmic reticulum (ER). PPi, inorganic phosphate. PA-Pase, phosphatidic acid phosphatase. PA-TP, phosphatidic acid transport protein. PtdIns-TP, phosphatidylinositol transport protein. CDP-DAG, cytidine diphosphate-diacylglycerol. CMP, CDP and CTP, cytidine mono-, di- and triphosphate, respectively.

These enzymes generate cyclic ADP-ribose and 2-phospho-cyclic ADP-ribose from NAD and NADP, respectively. Both molecules trigger cyclic ADP-ribose cytosolic Ca elevation, presumably by activating the ryanodine receptor in the endoplasmic/sarcoplasmic reticulum (Poliak et al. 2007). In addition to cyclic ADP-ribose, niacin adenine dinucleotide phosphate, a metabolite of NADP, can also mobilize stores. The release mechanism and the stores on which niacin adenine dinucleotide phosphate acts are from lysosomal Ca " stores, which are independent of the stores of activated by cyclic ADP-ribose or inositol 1,4,5-trisphosphate (Yamasaki et al. 2004). 

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