Figure 103

The role of diacylglycerol (DAG) and inositol triphosphate (Ins 1,4,5 P3) as second messengers linked to agonist-receptor (a±-adrenoceptor) interactions. Ptdins 4,5 P2 is a phosphatidylinositol precursor in cell membranes that is hydrolyzed following receptor activation to form the two second messengers, Ins 1,4,5 P3 and DAG. Once liberated within the cell, these second messengers activate separate but interacting pathways. Ins 1,4,5 P3 releases Ca++ stored in cells and can be phosphorylated to form a tetraphosphate (Ins 1,3,4,5 P4), which can open Ca++ channels in the membrane. DAG triggers protein phosphorylation through the activation of protein kinase C. Ca++-induced activation of the enzyme calmodulin also phosphorylates protein. Adenylyl cyclase traverses the membrane. Cyclic AMP-dependent protein kinase can phosphorylate and inactivate the (3-adrenoceptors. This kinase may have a role in homologous desensitization of Gs-protein-coupled (3-adrenoceptors. (3-Receptor stimulation can (1) activate Ca++ channels through an action of Gs proteins without the participation of cAMP and (2) affect other ion channels through phosphorylation via kinases. (Modified from Berridge MJ. Inositol triphosphate and diacylglycerol: Two interacting second messengers. ISI Atlas of Science: Pharmacology, 1:91, 1987.)

signal pathways. For example, inositol triphosphate functions by mobilizing calcium from intracellular stores or opening channels; the calcium can be used to initiate vascular smooth muscle contraction, probably through a protein phosphorylation pathway (Fig. 10.3). Diacylglycerol is known to stimulate an enzyme, protein kinase C, that phosphorylates specific intracellular proteins, some of which regulate ionic mechanisms such as the Na+/H+ exchanger and potassium channels.

The basic features of the signaling system found in different cells are remarkably similar. It appears that protein phosphorylation is a final common pathway in the molecular mechanisms through which neurotrans-mitters, hormones, and the nerve impulse produce many of their biological effects in target cells.

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