Inositol triphosphate diacylglycerol receptor system

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. 

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. 

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). 

Other receptor systems are coupled via GTP-binding proteins (G ), which activate phospholipase C. Activation of this enzyme releases the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG) from the membrane phospholipid phosphatidylinositol bisphosphate (P1P2). The IP3 induces release of Ca2+ from the sarcoplasmic reticulum (SR), which, together with DAG, activates protein kinase C. The protein kinase C serves then to phosphorylate a set of tissue-specific substrate enzymes, usually not phosphorylated by protein kinase A, and thereby affects their activity. 

The main signal transduction mechanism for PTH receptor stimulation is the cAMP system. Stimulation of renal or bone PTH receptors causes an elevation of membrane-bound and guanyl nucleotide-dependent adenylate cyclase activity resulting in the enhanced formation of cAMP from ATP. Recent studies suggest that PTH may also stimulate inositol triphosphate and diacylglycerol production in renal tissue (7). 

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.)...

The biological effects of histamine (Table 15.1) are mediated via three receptor subtypes, HI, H2 and H3 that are linked to G protein but activate different cell-signalling systems. The histamine HI receptor is associated with the phospholipase C-catalysed formation of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). The H2-receptor is coupled to adenylyl cyclase, increasing the production of cAMP. The cellular messenger system involved in H3-receptor activation has not been fully defined, but it may couple to N-type Ca2+-channels. The genes encoding for HI and H2 receptors have been cloned. A mutation of the human H2 receptor has been linked to schizophrenia. 

---