Signal transduction intracellular release mechanisms

The smooth muscle cell does not respond in an all-or-none manner, but instead its contractile state is a variable compromise between diverse regulatory influences. While a vertebrate skeletal muscle fiber is at complete rest unless activated by a motor nerve, regulation of the contractile activity of a smooth muscle cell is more complex. First, the smooth muscle cell typically receives input from many different kinds of nerve fibers. The various cell membrane receptors in turn activate different intracellular signal-transduction pathways which may affect (a) membrane channels, and hence, electrical activity (b) calcium storage or release or (c) the proteins of the contractile machinery. While each have their own biochemically specific ways, the actual mechanisms are for the most part known only in outline. 

Sulfation in most aspects is very similar to phosphorylation, except that sulfation is not involved in intracellular signal transduction, but in other forms of signaling. The mechanism of sulfation is similar to that of phosphorylation as a general base from the enzyme active site that deprotonates the hydroxyl groups of tyrosine residues. The nucleophilic oxygen then attacks the /3-position, in contrast to the 7-position in phosphorylation, and releases adenosine 3, 5 -diphosphate. 

The signal transduction mechanisms triggered by binding of ET-1 to its vascular receptors include stimulation of phospholipase C, formation of inositol trisphosphate, and release of calcium from the endoplasmic reticulum, which results in vasoconstriction. Conversely, stimulation of PGI2 and nitric oxide synthesis results in decreased intracellular calcium concentration and vasodilation. 

The studies of mast cell cytokine production described above have shown that maximal induction of cytokine synthesis and release usually occurs in response to IgE-dependent activation. In common with many cell types, there is evidence that FccRI on mast cells is coupled to the phospholipase C effector system that controls two distinct signal transduction pathways, one regulated by Ca " ions and the other by protein kinase C (PKC). Exocytotic degranulation is associated with an increased cytoplasmic level of Ca ions, and activation of mast cells can be therefore achieved by the use of calcium iono-phores which raise intracellular calcium concentrations through a receptor-independent mechanism. Alternative mast cell stimuli include phorbol-12-myristate-13-acetate (PMA) which activates PKC and induces mediator secretion from basophils and rodent mast cells but not from human mast cells, and concanavalin A (Con A), a lectin which can stimulate mast cells by cross-linking of cell-bound IgE and/or cell surface glycoproteins. 

HTia autoreceptor is inhibitory in nature thus, it responds to synaptic serotonin and inhibits, through a cascade of intracellular signal transduction, the depolarization of the cell, and, finally, it inhibits the release of serotonin from nerve terminals. Hence, when pindolol is administered, it inhibits the autoinhibition caused by 5-HTia receptors and thereby causes a net increase in synaptic 5-HT concentration. There is good evidence that facilitation of serotonergic neurotransmission may act either directly or indirectly as a unifying mechanism of antidepressant treatment. 

The mechanism of cardiac contraction involves a G-protein signal transduction pathway, which regulates intracellular calcium concentrations. Activation of the Gs-protein involves the formation of intracellular cAMP, which thereby increases intracellular calcium, stimulating cardiac muscle contraction (see Chapter 4). Relaxation occurs when the released cAMP is hydrolyzed by cytosolic cAMP-dependent PDE3, one of the phosphodiesterase isofoms. Therefore, inhibition of PDE3 increases intracellular cAMP, promoting cardiac muscle contraction but vasodilation of vascular smooth muscle. (See Chapter 17 for more information about phosphodiesterases.)... 

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