Signal transduction intracellular receptors

Another class of receptors mediate intracellular responses through Ca2+ mobilisation. A specific class of phospholipids, the phosophoinositides play an important role in signal transduction from receptors at the plasma membrane. The cellular responses that use phosphoinositide hydrolysis and Ca2+ mobilisation are diverse, they include general metabolism, secretion, contraction, phototransduction and proliferation. An imbalance of the second messenger system in the proliferation cascade may be responsible for normal cells becoming cancerous. 

The opposing effects on smooth muscle (A) of a- and p-adrenoceptor activation are due to differences in signal transduction, ai -Receptor stimulation leads to intracellular release of Ca2+ via activation of the inositol trisphosphate (IP3) pathway. In concert with the protein calmodulin, Ca2+ can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin (— vasoconstriction). 012-Adrenoceptors can also elicit a contraction of smooth muscle cells by activating phospholipase C (PLC) via the py-subunits of G, proteins. 

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. 

G-protein-coupled receptors (GPCRs), although some of them additionally play a role in intracellular signal transduction. Sphingosine-1-phosphate (SIP) and... 

The RTK activity phosphorylates tyrosine residues within the intracellular domain of the receptor. These phosphorylated residues function as docking sites for proteins that will convey the signal to downstream signal transduction components. PKI can be developed that bind these phosphorylated docking sites in order to abrogate inappropriate downstream signalling. 

Smad anchor for receptor activation) An intracellular protein Sara which accumulates at early endosomes and plays a key role in TGF- 3 signal transduction through the recruitment of receptor activated R-Smads for phosphorylation by the type ITGF-B receptor. 

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. 

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

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