Phosphatidyl inositol-3,4,5-triphosphate

Fig. 2. Major mechanisms involved in [i-AR desensitization and internalization. AP2, adaptor protein 2 p-ARK, P-adrenergic receptor kinase PI3K, phosphatidylinositol-3 kinase PIP3, phosphatidyl-inositol-3,4,5-triphosphate. (See Color Plate 3 following p. 148.)...

Cdt is related to a eukaryotic cytosolic enzyme, phosphatidyl inositol-3,4,5, triphosphate 5-phosphatase which removes the 5-phosphate group from phosphatidyl inositol-3,4,5, triphosphate. This activity is part of an intracellular signaling cascade induced by a ligand binding to a nearby receptor. Phosphatidyl inositol-3,4,5-triphosphate 5-phosphatase possesses an Src Homology 2 (SH2) domain in addition to its Inositol Phosphatase activity (SHIP). 

Glycerophospholipids are used for membrane synthesis and for producing a hydrophilic surface layer on lipoproteins such as VLDL. In cell membranes, they also serve as a reservoir of second messengers such as diacylglycerol, inositol 1,4,5-triphosphate, and arachidonic acid. Their structure is similar to triglycerides, except that the last fatty acid is replaced by phosphate and a water-soluble group such as choline (phosphatidylcholine, lecithin) or inositol (phosphatidyl-inositol). 

Cleavage of inositol-containing phospholipids by phospholipase C is of particular regulatory importance. Phospholipase C catalyzes the release of diacyl glycerol and inositol-l,4,5-triphosphate from phosphatidyl inositol-4,5-diphosphate, a phospholipid... 

Fig. 5.24 Classification of the phospholipases and the reaction of phospholipase C. a) Cleavage specificity of phospholipases Al, A2, C and D. b) Cleavage of inositol-containing phosphohpids by phospholipase C. In a reaction of particnlar importance for signal transduction, phosphohpase C (PL-C) catalyzes the cleavage of phosphatidyl inositol-4,5-bisphosphate (PtdIns(4,5)P2) into the messenger substances diacylglycerol and inositol 1,4,5-triphosphate (Ins(l,4,5)P3).

The interaction of certain members of the G protein family with an enzymatic activity known as phospholipase C results in the hydrolysis of the membrane phospholipid, phosphatidyl inositol, into diacylglycerol (DAG) and inosine triphosphate (IP3) shown in Fig. 4.9C (Ross, 1992a Kennedy, 1992 Hardie, 1991). DAG is an activator of the protein kinase C family of enzymes discussed below, and acts by reducing the level of calcium needed for their activation. (Several diacylglycerols, depending on the exact... 

FIGURE 9.98 Events taking place in the plasma membrane on stimulation of a cell. Phospha tidylinositol (Pi) and more hi ly phosphoiylated versions of this lipid account for 2 to 8% of the lipids of the plasma membrane of eukaryotic cdIs. The inositol 1,4,5 triphosphate (fP3) moiety of phosphatidyl inositol- 4,8-di phosphate may be hydiulyitec from this lipid immediately after the cell is stimulated. For example, the stimulation of platelets by thrombin or the islets of the pancreas by glucose is followed by the release of 1P3 into the cytoplasm. In some cells, arachidonic acid is hydrolyzed from l-acyl-2-arachidonyl-glyceroL which can Support a burst of prostaglandin. synthesis. 

The answer is c. (Murray, pp 238-249. Scriver, pp 2367-2424. Sack, pp 159-175. Wilson, pp 287-317.) A variety of agonists activate the plasma membrane-bound enzyme phospholipase C, which hydrolyzes the phosphodiester bond of phosphatidyl inositol 4,5-bisphosphate and consequently releases diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). Phospholipase C is also known as phosphoinositidase and as polyphosphoinositide phosphodiesterase. Both DAG and IP3 are second messengers. DAG activates protein kinase C, which is important in controlling cell division and cell proliferation. IP3 opens calcium channels and allows the rapid release of the calcium stores in endoplasmic reticulum (in smooth muscle, sarcoplasmic reticulum). The elevated levels of calcium ion stimulate smooth-muscle contraction, exocytosis, and glycogen breakdown. 

Lithium decreases production of adenosine 3c,5c-cyclic monophosphate (cAMP), and inhibits the recycling of phosphatidyl inositol phosphate to inositol, resulting in a decrease in inositol triphosphate (IP3). Lithium also affects the permeability of membranes to sodium and potassium. 

Neuronal and hormonal signals may often be transduced via receptor-mediated activation of phophoinositidase C (inositol lipid-directed phospholipase C), which converts phosphatidyl-inositol 4,5-bisphosphate (PIP2) to 1,2-diacyl-glycerol (1,2 DG) and D-inositol 1,4,5-triphosphate [(1,4,5)IP3] in the cell membrane. These metabolic products are second messengers 1,2 DG stimulates protein kinase C and (1,4,5)IP3 releases intracellular calcium from the endoplasmic reticulum. Subsequently, (1,4,5)IP3 is ultimately converted to myoinositol. That in turn is converted to phosphatidylinositol, which is used to replenish PIP2 stores and thus complete the cycle. ... 

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