G-Proteins and Signal Transduction

The signal transduction G-proteins or heterotrimeric GTP binding proteins, are interposed between cell siuface receptors and intracellular effectors. The signal tran uction G-proteins are a family of GTP-binding proteins in which the GTP-GDP switch serves to propagate and amplify regulatory signals from activated cellular membrane receptors to effector channels and enemies. 

G-protein linked receptors, sometimes referred to as seven membrane spanning serpentine receptors include, as their name suggests, seven membrane-spanning sequences. Sites of receptor/G-protein interaction are within cytoplasmic and possibly membrane spanning sequences. Recent evidence indicates that die carboiqrl terminal portion of the third intracellular loop and the carbojqrl terminal portion of the receptor are the likely sites of interaction.(Bimbaumer, Bimbaumer, 1995). 

Although none of the G-protein subunits contains regions that might obviously associate with a lipid bilayer, heterotrimeric G-proteins are associated with the cytoplasmic surface of the plasma membrane as is Ras p21 and some of the other low molecular weight GTP-binding proteins. This is apparendy due to the fact that the y-subunits of the heterotrimeric G-proteins are prenylated, as is ras, and at least some of the G-protein a-subunits, e.g. Gj subfamily. 

Some of the G rroteins are substrates for ADP-ribosylation by bacterial toxins. Specifically, toxins from Vibrio cholera, cholera toxin (CT) or Bordetella pertussis, pertussis toxin (PT), can covalently modify the G roteins by addition of an ADP-ribose 

Nine heterotrimeric G-proteins have been identified in platelets. One (G from the G, family, four (Gj, Gfaj. Gj,3 and p ) from the p fiimily, two (p, and p, ) fix)m the p mily and two (G,3 and GjjJ fix m the G,2 femily (Akkerman, Van Willigen, 1996 Brass etal, 1997). 

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See also Substrate Level Phosphorylation, Nucleotide Salvage Synthesis, De Novo Biosynthesis of Purine Nucleotides, Nucleotides, Guanine, G Proteins and Signal Transduction... 

See also Kinase Cascade, G Proteins and Signal Transduction, G Proteins in Vision, Kinase Cascade in Fat Mobilization (from Chapter 18)... 

See also Viral and Cellular Oncogenes, Oncogenes in Human Tumors, G Proteins and Signal Transduction, G Protein Families and Subunits, Receptors with Protein Kinase Activity, Hormone Action... 

See also G Proteins and Signal Transduction, Hormone Mechanisms of Action, Guanylate Cyclase... 

FIGURE 14-6 Main signaling pathways for histamine receptors. Histamine can couple to a variety of G-protein-linked signal transduction pathways via its four different receptors. The Hj receptor activates the phosphatidylinositol turnover via Gq/11 proteins. The other receptors either positively (H2 receptor) or negatively (H3 and H4 receptor) regulate adenylyl cyclase activity via Gs and GUo protein activation respectively. Several additional signaling pathways have been described, which are not shown. Abbreviations PfP2, phosphatidylinositol 4,5-bisphosphate PIC, phospholipase C AC, adenylyl cyclase ATP, adenosine triphosphate cAMP, cyclic AMP PKC, protein kinase C PICA, protein kinase A. 

GM-CSF and IL-3 have been shown to compete for receptors in some types of cells (e.g. eosinophils and KG-1 cells), indicating some structural homology between GM-CSF and IL-3 receptors, perhaps because they share certain subunits or adapter proteins. GM-CSF occupancy results in phosphorylation of certain proteins, and because the receptor possesses no inherent kinase activity, receptor occupancy must be linked to kinase activity via the generation of second messenger molecules. Pretreatment of cells with pertussis toxin abolishes the effects of GM-CSF, indicating the involvement of G-proteins in signal transduction. Priming of neutrophil functions with GM-CSF involves the activation of phospholipases A2 and D. 

Weingarten, R., Bokoch, G. M. (1990). GTP binding proteins and signal transduction in the human neutrophil. Immunol. Lett. 26, 1-6. 

Spiegel, A. M. (1998) Introduction to G-protein-coupled signal transduction and human disease, in G proteins, receptors, and disease (A. M. Speigel, ed.), Humana Press, Totowa, NJ,... 

It is likely that phosducins play a role in many G-protein coupled signal transduction pathways. Phosducin-like proteins have been identified in a variety of tissues, e.g., in brain and in the pineal gland. 

There is evidence that signals starting from G-protein-coupled receptors run into the Ras switch station (Van Biesen et al., 1995). Pv-subunits of G-proteins are under discussion as the link between G-protein-coupled signal transduction and the Ras pathway these subunits could influence the activity of Ras protein and the subsequent MAP kinase pathway by a presently unknown mechanism. 

Simon, M. I., P. Strathmann, and N. Gautam, Diversity of G proteins in signal transduction. Science 252 802-808,... 

Hashim, S., Y.Y. Liu, R. Wang, and M.B. Anand-Srivastava. 2002. Streptozotocin-induced diabetes impairs G-protein linked signal transduction in vascular smooth muscle. Mol. Cell. Biochem. 240 57-65. 

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

Figure 21.14. Regulatory Cascade for Glycogen Breakdown. Glycogen degradation is stimulated by hormone binding to 7TM receptors. Hormone binding initiates a G-protein-dependent signal-transduction pathway that results in the phosphorylation and activation of glycogen phosphorylase.

This GTP-GDP cycle of EF-Tu is reminiscent of those of the heterotrimeric G proteins in signal transduction (Section 15.1.2) and the Ras proteins in growth control (Section 15.4.2). This similarity is due to their evolutionary heritage, inasmuch as the amino-terminal domain of EF-Tu is homologous to the P-loop NTPase domains in the other G proteins. 

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. 

Fig. 3. The G-protein dependent signal transduction cycle. The signal transduction unit is represented by R (receptor), G (G protein), and E (effector). G is composed of Ga wifh bound GTP or GDP and of GPy. The acfive and inactive complexes or proteins are shown in black and grey, respectively. S represents the stimulus that triggers the cycle. Proteins interacting in a complex ore linked by hyphens...

Mammalian pheromones released into their environment can readily reach their target tissue, either the main olfactory epithelium (MOE) or the VNO. Both target tissues are lined with an olfactory neuroepithelium that contains membrane-bound receptor proteins, which comprise the largest known family of G-protein-coupled [262] receptors in mammals. The number of mammalian olfactory receptors [263-265] found has been astonishing, but not unreasonable. The MOE and VNO have some common features, but also significant difierences in neuron types, primary structures of receptor proteins and signal transduction [266]. 

Childers, S.R. Pacheco, M.A. Bennett, B.A. Edwards, T.A. Hampson, R.E. Mu, J. and Deadwyler, S.A. Cannabinoid receptors G-protein-mediated signal transduction mechanisms. Biochem Soc Symposia 59 27-50, 1993. 

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