Phosphatidylinositol system

FIGURE 12-19 Hormone-activated phospholipase C and IP3. Two intracellular second messengers are produced in the hormone-sensitive phosphatidylinositol system inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. Both contribute to the activation of protein kinase C. By raising cytosolic [Ca2+], IP3 also activates other Ca2+-dependent enzymes thus Ca2+ also acts as a second messenger. 

Phosphatidylinositol system G protein linked secondary messenger system which,... 

Decrease in blood pressure Injection of acetylcholine causes vasodilation and the lowering of blood pressure. Although no innervation of the vasculature by the parasympathetic system exists, there are cholinergic receptors on the blood vessels that respond by causing vasodilation. The vasodilation is due to an acetylcholine-induced rise in intracellular Ca++—caused by the phosphatidylinositol system—that results in the formation of nitric oxide (NO) from arginine in endothelial cells.2 [Note NO is also known as endothelium-derived relaxing factor (EDRF).] (See p. 176 for more detail on nitric oxide.) In the absence of adminis-... 

None of the available oral phosphodiesterase inhibitors has become established in routine therapy, because the short-term benefit of the increased contractility has been offset by an increased mortality (presumably due to arrhythmias) on chronic dosing. A similar fate befell flosequinan, a positive inotrope which acted through the phosphatidylinositol system. Their use is restricted to short-term symptom control prior to, for example, transplanation. 

Figure 4 Schematic representation of the Ca2+-transporting systems affecting cellular calcium homeostasis during hormonal stimulation, oq = oq-adrenergic receptor VP = vasopressin receptor PLC = phospholipase C PI = phosphatidylinositol PIP = phospha-tidylinositol-4-phosphate PIP2 = phosphatidylinositol-4,5-biphosphate IP3 = inositol-1,4,5-triphosphate DG = diacylglycerol PKC = protein kinase C. (Modified from Refs. 125 and 285.)...

Other enzymes present in myelin include those involved in phosphoinositide metabolism phosphatidylinositol kinase, diphosphoinositide kinase, the corresponding phosphatases and diglyceride kinases. These are of interest because of the high concentration of polyphosphoinositides of myelin and the rapid turnover of their phosphate groups. This area of research has expanded towards characterization of signal transduction system(s), with evidence of G proteins and phospholipases C and D in myelin. 

A1 adenosine receptors are inhibitory in the central nervous system. A receptors were originally characterized on the basis of their ability to inhibit adenylyl cyclase in adipose tissue. A number of other G-protein-mediated effectors of A receptors have subsequently been discovered these include activation of K+ channels, extensively characterized in striatal neurons [13], and inhibition of Ca2+ channels, extensively characterized in dorsal root ganglion cells [14]. Activation of A receptors has been shown to produce a species-dependent stimulation or inhibition of the phosphatidylinositol pathway in cerebral cortex. In other tissues, activation of A receptors results in synergistic activation of the phosphatidylinositol pathway in concert with Ca2+-mobilizing hormones or neurotransmitters [15]. The effectors of A adenosine receptors and other purinergic receptor subtypes are summarized in Table 17-2. 

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... 

Frosolono and Currie (1985) investigated the effect of phosgene on the pulmonary surfactant-system (PSS) in groups of six to 14 rats exposed to phosgene at 1 ppm for 4 h. The exposure system and parameters were similar to those described in Section 3.2.1 (Hatch et al. 1986). The actual chamber concentration was 1.0 0.06 ppm. Animals were sacrificed immediately after exposure, or on postexposure days 1, 2, or 3. Pulmonary edema was present immediately after exposure and persisted through day 3. Phosphatidylinositol levels were significantly (p<0.05) decreased compared with controls immediately after exposure only. Phosphatidylserine and phosphatidylethanolamine levels were significantly increased compared with controls on days 1, 2, and 3 postexposure. Phosphatidylcholine levels were increased at all time points compared with controls. 

PTHrP). The receptor signal is mediated by G proteins that activate adenylyl cyclase and the phosphatidylinositol-calcinm second-messenger system. Mntations of PTHRl are associated with abnormalities of development related to altered PTHrP ligand binding. PTHrP is a key paracrine peptide responsible for osteochondrogenesis dnring fetal development (55,56). 

Lithium inhibits inositol monophosphate and decreases brain levels of inositol. Belmaker s group [see Levine et ah. Chapter 9, in this volume) showed a selective therapeutic effect of inositol in patients with either depression or panic disorder. Because of the possible importance of the second-messenger system of the phosphatidylinositol [PI) cycle in mood regulation, and because of its influence by lithium, it would be of future in-... 

I nositol is a simple substance present normally in the diet at about 1 g/day and is an isomer of glucose. The phosphatidylinositol (PI) cycle is an important second messenger system for several brain neurotransmitters (Figure 9-1). Receptor (R) stimulation by an activator (A) leads to breakdown of membrane phosphatidylinositol 4,5-biphosphate (PIP2) to... 

M.D. Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 p protein by using the baculovirus expression system. Biochem. J., 288, 395-405 (1992)... 

These studies all support the hypothesis that external stimuli of the elicitor cause an increase in the cytoplasmic Ca2+ level via the phosphatidylinositol cycle and/or the adenylate cyclase system. Although an authoritative picture of this process cannot yet be given, possible signal transduction mechanisms are summarized in Fig. (2). At present the data... 

Fig. 20.3. Schematic representation of the main pathways in the lipid metabolism of parasitic flatworms. Boxed substrates are supplied by the host. Pathways present in mammalian systems but absent in parasitic flatworms are shown by open arrows. Abbreviations DAG, diacylglycerol CDP-DAG, cytidine diphosphodiacylglycerol Farnesyl PP, farnesyl pyrophosphate Geranyl PP, geranylpyrophosphate Geranylgeranyl PP, geranylgeranylpyrophosphate FlMG-CoA, hydroxymethylglutaryl-CoA TAG, triacylglycerol PA, phosphatidic acid PC, phosphatidylcholine PE, phosphatidylethanolamine PI, phosphatidylinositol PS, phosphatidylserine.

In primary cultures of neonatal cerebellar granule neurons, all Ca2+ sensors, calmodulin, protein kinases C (PKC), and the p21(ras)/phosphatidylinositol 3 -kinase (Ptdlns-3K)/Akt pathway, converge towards NF-kB at the levels of nuclear translocation as well as transcription. The duration of NF-kB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on the different upstream and downstream signaling associated with various kinases. This is in contrast to studies in non-neuronal cells, which either do not respond to Ca2+ or do not simultaneously activate all three cascades (Lilienbaum and Israel, 2003). Collective evidence suggests that brain inflammatory processes differ from systemic inflammation not only in the involvement of various types of neural cells but also in differences in response to second messengers. 

Effect of lithium on the IP3 and DAG second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PIP2, phosphatidylinositol-4,5-bisphosphate PLC, phospholipase-C G, coupling protein EFFECTS, activation of protein kinase C, mobilization of intracellular Ca2+, etc.) Lithium, by inhibiting the recycling of inositol substrates, may cause... 

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