Hydrolysis of phosphatidylinositol

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. 

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 ]. 

The cq receptors are activated not only by catecholamines but also by the hormones vasopressin and angiotensin n. Binding of these hormones to a, receptors induces a complex response that involves rapid hydrolysis of phosphatidylinositol derivatives and release of Ca2+ into die cytoplasm, and of diacylglycerols into the lipid bilayer of the membrane. The response is mediated by another G protein called Gq.27 1 275 When this G protein is activated it induces the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2), a normal minor component of the lipid bilayer, by phospholipase C (phosphoinositidase C).265,276 281... 

After activation of the TCR, there is induction of Src family tyrosine kinase (p56lek), which phosphorylates phospholipase Oyl. This is followed by the hydrolysis of phosphatidylinositol 4,5-bisphosphate, resulting in the production of diacyl-glycerol (DAG) and inositol trisphosphate (IP3). Protein kinase C is activated by DAG, which phosphorylates Ras. Ras is a GTPase and its phosphorylation induces Raf and initiation of MAP kinase signaling pathway. IP3 is involved in calcium-dependent activation of IL-2 gene expression via nuclear factor of activated T cells (NFAT). 

Uncoating requires an interaction with the uncoating ATPase Hsc70. Apparently, however, hydrolysis of phosphatidylinositol (4,5)-bisphosphate is required, which is carried out by the protein synaptojanin. Synaptojanin has two phosphatase domains, and in its absence clathrin-coated vesicles accumulate. Furthermore, the... 

IP3 and DAG are derived from the membrane lipid phosphatidylinositol 4,5-bisphosphate (which is a phosphorylated derivative of phosphatidylinositol see Topic El) by the action of phospholipase C which is also located in the plasma membrane and, like adenylate cyclase, is activated by G proteins (Fig. 5). One of the main actions of the polar IP3 is to diffuse through the cytosol and interact with Ca2+ channels in the membrane of the ER (Fig. 5), causing the release of stored Ca2+ ions which in turn mediate various cellular responses. The DAG produced by the hydrolysis of phosphatidylinositol 4,5-bisphosphate, along with Ca2+ ions released from the ER, activates protein kinase C, a membrane-bound enzyme that phosphorylates various target proteins, again leading to alterations in a variety of cellular processes (Fig. 5). 

Fisher, G.J., Talwar, H.S., and Baldassare, J.J., Increased phospholipase C-catalysed hydrolysis of phosphatidylinositol-4, 5-bisphosphate and 1, 2-sn-diacylglycerol content in psoriatic involved compared to uninvolved and normal epidermis, J. Invest. Dermatol., 95, 428, 1990. 

Unlike some other hormones which act on the adrenal cortex, such as angiotensin II and acetylcholine, ACTH probably does not have a major portion of its action via the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and the gen-... 

A signal transduction pathway in which hormone binding to a cell surface receptor induces phospholipase C to catalyze the hydrolysis of phosphatidylinositol bisphosphate to yield the second messengers inositol... 

Figure 7, Phospholipase C-mediated hydrolysis of phosphatidyl inositol 4,5-bisphos-phate. Phosphoinositide-specific phospholipase C is activated during cellular stimulation and mediates the hydrolysis of phosphatidylinositol 4,5-bisphosphate. The two products of this reaction, DAG and IP3, are both intracellular second messengers. Thus, a single hydrolytic reaction initiates a bifurcating pathway of signal transduction mediated by protein kinase C activation and calcium mobilization, respectively.

Answer C. Muscarinic receptors present in bronchiolar smooth muscle are of the M3 subtype coupled via Gq proteins to phospholipase C. Activation of this enzyme causes hydrolysis of phosphatidylinositol bisphosphate, with release of IP3 and DAG (the latter activates protein kinase C). Decreased formation of cAMP mediated via a G protein occurs with activation of M2 receptors such as those in the heart. Cation channel opening occurs in response to activation of nicotinic receptors. 

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].

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