G protein mediated signal transduction

An exciting development in G-protein-mediated signal transduction research has been the realization that proteins produced by oncogenes (cancer-causing genes) are also GTP-binding proteins. 

Childers SR, Pacheco MA, Bennett BA, Edwards TA, Hampson RE, et al. 1993. Cannabinoid receptors G-protein-mediated signal transduction mechanisms. Bio-chem Soc Symp 59 27-50. 

G-protein mediated signal transduction cascades (Pugh and Lamb 2000 Okada et al. 

Platelets from SHR exhibit increased sensitivity to thrombin and PGE, than platelets from WKY rats. Both of these agonists produce their effects by a G protein mediated signal transduction mechanism leading to activation of PI-PLC and adenylyl cyclase respectively. Enhanced signal transduction at the G protein level may be responsible for a greater adenylyl cyclase, and possibly PI-PLC, activity in SHR than in WKY platelets. 

The CBl and CBj cannabinoid receptors in nervous, immune, and other tissues of the body participate in G protein-mediated signal transduction pathways. Particularly well characterized are those that regulate the second messengers cyclic AMP, Ca ", and perhaps IP3. CBi receptors are modulators of ion channels, which makes them key players in the control of neurotransmission. These receptors also partic-... 

Rasenick MM, Chaney KA, Chen J. G-protein-mediated signal transduction as a target of antidepressant and antibipolar drug action Evidence from model systems. J Clin Psychiatry 1996 57(suppl 13) 49-55 discussion 56-58. 

Figure 4.11. Receptor G-protein-mediated signal transduction, (a) Receptor (i ) associates with a specific ligand (L), stabilizingan activated form of the receptor (R ), which can catalyze the exchange of GTP for GDP bound to the a-subunit of a G-protein. The jSy-heterodimer may remain associated with the membrane through a 20-carbon isoprenyl modification of the y-subunit. The receptor is desensitized by specific phosphoiylation (-P). (b) The G protein cycle. Pertussis toxin (PTX) blocks the catalysis of GTP exchange by receptor. Activated a-subunits (aGTP) and /Sy-heterodimers can interact with different effectors (E). Cholera toxin (CTX) blocks the GTPase activity of some a-sub-units, fixing them in an activated form.

DHA is very abundant in excitable membranes in the retina and brain, particularly in PL of the rod outer segment of retina and of synaptic vesicles, and is important in vision. However, the mechanism by which DHA functions in retina is not well understood. Chen et al. (Y. Chen, 1993) suggest that DHA in retina might be involved in shuttling 11-c/j-retinal to photoreceptors, whereas Niu et al. (S. Niu, 2004) propose that DHA in PL increases the efficiency of G-protein-mediated signal transduction of rhodopsin. In humans, supplementation of infant formula with DHA accelerates the development of visual functions in pre-term infants. The novel protective lipid mediator docosanoids, namely, Protectin D1 (C. Serhan, 2002) and 17S-hydroperoxy-DHA (V. Marcheselli, 2003), have been suggested to mediate the beneficial effects of DHA. 

Figure lOJ Summary of secondary metabolite gene regulation via G protein-mediated signal transduction. The indicated positive and ne tive regulation (arrows and bars, respectively) has been found to be mediated transcriptionally, post-transcriptionally, or by both mechanisms, as described in the text. 

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. ...

Noradrenaline acts on three types of receptor. The ai receptors mediate the main excitatory effects of noradrenaline upon wake-active neurons in the dorsal raphe, basal forebrain, and elsewhere (Vandermaelen Aghajanian, 1983 Nicoll, 1988 Fort et al., 1995 Brown et al., 2002). The a2 receptors mediate inhibitory effects of noradrenaline, e.g. on noradrenaline neurons themselves and on cholinergic brainstem neurons (Williams et al., 1985 Williams Reiner, 1993). The (3-receptors modulate neurons in a more subtle fashion, increasing excitability via blockade of afterhyperpolarizations in hippocampal and cortical neurons (Haas Konnerth, 1983). Activation of (3-receptors also promotes synaptic plasticity via activation of the cyclic-AMP-dependent kinase (PKA) and cyclic AMP response element binding protein (CREB) signal transduction pathway (Stanton Sarvey, 1987 Cirelli et al., 1996). 

An, S., Bleu, T. and Zheng, Y., 1999, Transduction of intracellular calcium signals through G protein- mediated activation ofphosphohpase C by recombinant sphingosine 1- phosphate receptors. Mol. Pharmacol. 55 787-794. 

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