Diacylglycerol second messenger systems

FIGURE 52-2 There are two modes of hormonal action. (A) Activation of cell-surface receptors and coupled second-messenger systems, with a variety of intracellular consequences. (B) Entry of hormone into the target cell, binding to and activation of an intracellular receptor and binding of the receptor-hormone complex to specific DNA sequences to activate or repress gene expression. DAG, diacylglycerol HRE, hormone-response element. 

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. 

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). 

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. 

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. 

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. 

Fig. 1. A model for the pleiotropic effects of LH on functions of Leydig cells. LH interacts with its specific receptor in the plasma membrane of the Leydig cell which results in the activation of several transducing systems and the formation of several second messengers (cyclic AMP, Ca2+, diacylglycerol and arachidonic acid metabolites). Protein kinases (A, C and calmodulin dependent) are activated resulting in the phosphorylation of specific proteins and the synthesis of specific proteins. The (phospho)proteins are involved in the transport of cholesterol to, and the control of, cholesterol metabolism in the inner mitochondrial membrane. Arachidonic acid metabolites (prostaglandins, leukotrienes) may also control steroidogenesis. LH can also regulate the secretion of proteins. The trophic effects of LH are manifested in the growth and differentiation of the Leydig cells.

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