Phosphatidylinositol 2, 2 hydrolysis

Song F, Freemantle N, Sheldon TA Selective serotonin reuptake inhibitors meta-analysis of efficacy and acceptabihty. BMJ 306(6879) 683-687, 1993 Song L, Jope R Chronic lithium treatment impairs phosphatidylinositol hydrolysis in membranes from rat brain regions. J Neurochem 58 2200-2206, 1992 Souza EG, Mander AJ, Goodwin GM The efficacy of lithium in prophylaxis of unipolar depression evidenced from its discontinuation. Br J Psychiatry 157 718-722, 1990... 

Nakajima, Y., Tsuchida, K., Negishi, M., Ito, S., Nakanishi, S. Direct linkage of three tachykinin receptors to stimulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected Chinese hamster ovary cells, J. Biol. Chem. 1992, 267, 2437-2442. 

Berridge MJ. 1981 Phosphatidylinositol hydrolysis a multifunctional transducing mechanism. Mol Cell Endocrinol 24, 115-140. 

Cotecchia S, Ostrowski J, Kjelsberg MA, Caron MG, Lefkowitz RJ (1992) Discrete amino acid sequences of the alpha 1-adrenergic receptor determine the selectivity of coupling to phosphatidylinositol hydrolysis. J Biol Chem 267 1633-1639. 

Cotecchia S, Exum S, Caron MG, Lefkowitz RJ. Regions of the a,-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function. Proc Natl Acad Sci USA 1990 87 2896-2900. 

Clemente, R., Jones, D.R., Ochoa, P., Romero, G., Mato, J.M., and Varela-Nieto, 1. Role of glycosyl-phosphatidylinositol hydrolysis as a mitogenic signal for epidermal growth factor. Cell Signal,... 

J., and Varela-Nieto, I. Insulin-like growth factor-I regulates cell proliferation in the developing inner ear, activating glycosyl-phosphatidylinositol hydrolysis and Eos expression. Endocrinology, 1995,... 

Fig. 28.7 Dose-response curve for carbachol-mediated inhibition of cAMP formation and stimulation of phosphatidylinositol hydrolysis (PI) in cells expressing cloned m2-muscarinic receptors. (Reproduced with permission from reference 55.)...

Aluminum is reported to stimulate second messenger systems in the absence of F. McDonald and Mamrack (1988) identified an effect of A1 alone on phosphatidylinositol hydrolysis. While the phospholipase C that normally carries out this function is regulated by a G protein, their work involved the purified enzyme with no G-protein component. They found inhibition of hydrolysis of phosphatidylinositol-4,5-bisphosphate, but stimulation of the hydrolysis of phosphatidylinositol. The stimulation should therefore lead to diacylglycerol-dependent increases in intracellular Ca. Their work clearly showed that A1 and not AIF was the active factor, by using F to chelate A1 and reverse the stimulation. 

Another mechanism in initiating the contraction is agonist-induced contraction. It results from the hydrolysis of membrane phosphatidylinositol and the formation of inositol triphosphate (IP3)- IP3 in turn triggers the release of intracellular calcium from the sarcoplasmic reticulum and the influx of more extracellular calcium. The third mechanism in triggering the smooth muscle contraction is the increase of calcium influx through the receptor-operated channels. The increased cytosolic calcium enhances the binding to the protein, calmodulin [73298-54-1]. 

TRPVl, also known as the capsaicin- or vanilloid-receptor, is a nonselective cation channel expressed e.g., in neurons of the dorsal root and trigeminal ganglions, which integrates multiple pain-producing stimuli including heat, protons, capsaicin, and resiniferatoxin. In addition, TRPVl currents can be activated by ananda-mide, protein kinase C (PKC), and by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). 

Covalent regulation. Following occupation and activation of the M2 acetyl choline receptors, phospholipase C (PLC), is activated and both inositol (l,4,5)-trisphosphate (IP3), and diacylglycerol (DAG), are formed by hydrolysis of phosphatidylinositol (4,5)-bisphosphate (PIP2). 

Activation of Neutrophils Is Similar to Activation of Platelets Involves Hydrolysis of Phosphatidylinositol Bisphosphate... 

Inositol triphosphate (IP3)-gated channels are also associated with membrane-bound receptors for hormones and neurotransmitters. In this case, binding of a given substance to its receptor causes activation of another membrane-bound protein, phospholipase C. This enzyme promotes hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP2) to IP3. The IP3 then diffuses to the sarcoplasmic reticulum and opens its calcium channels to release Ca++ ions from this intracellular storage site. 

Berstein, G., Blank, J. L., Smrcka, A. V. etal. Reconstitution of agonist stimulated phosphatidylinositol 4-5 bisphosphate hydrolysis using purified mi muscarinic receptor, Gq/11, and phospholipase C-Pl. /. Biol. Chem. 267 8081-8088, 1992. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

When the receptor interacts with its associated G protein, the conformation of the guanine-nucleotide-binding site is altered. The subunits then dissociate, and a phosphatidylinositol-specific phospholipase C (PI-PLC) is activated [5]. The subsequent hydrolysis of phosphatidylinositol bisphosphate then produces inositol triphosphate (IP3) and diacylglycerol (DAG), which are known to be secondary messengers. For example, the water soluble IP3 is released into the cell where its ultimate targets are the calcium storage organelles from which Ca2+ is released [3]. The presence of DAG in cells is known to activate the cellular enzyme protein kinase C (PKC) [6, 7], which phosphorylates a number of cellular... 

The rate of production of DAG in the cell does not occur linearly with time, but rather it is biphasic. The first peak is rapid and transient and coincides with the formation of IP3 and the release of Ca2+ this DAG is therefore derived from the PI-PLC catalyzed hydrolysis of phosphatidylinositols [1]. There is then an extended period of enhanced DAG production that is now known to be derived from the more abundant phospholipid phosphatidylcholine (PC), which has a different composition of fatty acid side chains [9]. Although DAG may be generated directly from PC through the action of PC-PLC, it can also be formed indirectly from PC. In this pathway, PC is first hydrolyzed by PLD to give choline and phosphatidic acid, which is then converted to DAG by the action of a phos-phatidic acid phosphatase [10,11 ]. 

Figure 6.7. Phosphatidylinositol 4,5-bisphosphate hydrolysis by phospholipase C. Occupancy of receptors (R) results in exchange of bound GDP for GTP on the a-subunit of a het-erotrimeric G-protein. The a-subunit then dissociates from the fi- and y-subunits and activates phospholipase (PLC). This enzyme is calcium dependent and, upon activation, can hydrolyse phosphatidylinositol 4,5-bisphosphate (PIP2). The products of this hydrolysis are inositol 1,4,5-trisphosphate (Ins 1,4,5-P3), which is released into the cytoplasm, and diacylglycerol (DAG), which remains in the membrane. The DAG is an activator of protein kinase C, which moves from the cytoplasm to the membrane, where it forms a quaternary complex with DAG and Ca2+. 

Figure 6.9. Pathways of inositol phosphate metabolism. Ins 1,4,5-P3, generated via the hydrolysis of phosphatidyl 4,5-bisphosphate by phospholipase C, can be metabolised by a kinase (to generate Ins 1,3,4,5-P4) or via a phosphatase (to yield Ins 1,4-P2). These products can be metabolised further to produce inositol, which itself may be sequentially phosphory-lated to regenerate phosphatidylinositol 4,5-bisphosphate.

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