Inositol triphosphate diacylglycerol receptor

Another second messenger system, the inositol triphosphate-diacylglycerol system, can also be activated by cholinergic or adrenergic receptors. It involves calcium movement and will be discussed when and if time permits. 

The activated G-protein subunits detach from the receptor and initiate signalling from many downstream effector proteins, including phosphodiesterases, adenyl cyclase, phosphohpases and ion channels, which permit the release of second messenger molecules such as cychc adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositol triphosphate, diacylglycerol and calcium ions. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

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... 

Platelet activation occurs in large part via G protein-coupled agonist receptors and intracellular signaling events that involve activation of phospholipase C (PLC). PLC catalyzes the breakdown of plasma membrane inositol phospholipids, resulting in generation of 1,2-diacylglycerol (DAG) and 1,4,5-inositol triphosphate (IP3). DAG activates protein kinase C, and IP3 induces mobilization of calcium from intracellular stores (10). 

An additional action of Li" is interruption of the phosphatidylinositide cycle through an inhibitory action on inositol phosphate metabolism. By this mechanism, depletion of membrane inositol and the phosphoinosi-tide-derived second-messenger products diacylglycerol and inositol triphosphate ultimately reduces signaling through receptor systems dependent on the formation of these products. It is presently unclear to what extent inhibition of inositol phosphate metabolism contributes to the therapeutic properties of Li+ in bipolar patients. 

A number of presynaptic receptors are coupled to the activation of phospholipase C (PLC) through Gq (Majewski and Iannazzo 1998). PLC activation results in the production of two second messengers, viz. diacylglycerol (DAG) and inositol triphosphate (IP3). The former stimulates PKC together with Ca2+, while the latter initiates the release of Ca2+ from intracellular stores. As with PKA, PKC is pleiotropic in its effects, thus the specific regulation of presynaptic function necessitates the delineation of nerve-terminal-specific target proteins. Additionally, it has... 

Activation of receptor increases production of diacylglycerol and Inositol triphosphate leading to an increase in intracellular calcium ions. 

Figure 32.4. Cyclosporin A (CsA) disruption of signal transduction pathways leading to IL-2 production. CsA binds to cyclophilin in the cytoplasm. The complex disrupts at least two signaling pathways, decreasing activation of transcription factors AP-1 and NF-AT that lead to activation of genes involved in cytokine production. See text for detailed explanation. Abbreviations TCR, T-cell receptor PLC, phospholipase C IP3, inositol triphosphate PKC, protein kinase C DAG, diacylglycerol NF-AT, nuclear factor of activation PI, phophati-dylinositol PC, phosphatidylcholine.

Ach, HA, and gastrin stimulate acid secretion by activating specific receptors on the ba-solateral membrane of the parietal cell. Once bound to the respective G-protein-coupled receptor, second-messenger systems are activated. Ach and gastrin activate phospholipase C to catalyze the conversion of membrane-bound phospholipids to diacylglycerol and inositol triphosphate. The release of Ca from intracellular stores and the subsequent increase in cytoplasmic Ca + activates ATPase (proton pump). The binding of HA to the H2-receptor activates adenylate cyclase, resulting in an increase in cAMP, which activates the proton pump (11). 

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