G protein system

Figure 12.6 Effector mechanism activation of adenyi cyclase via a G-protein. The activation of adenyi cyclase, which resides on the cytosolic side of the cell membrane, is mediated through the membrane-bound G-protein system (see below for biochemistry and role of the G-protein). An example is adrenaline binding to the p-receptor.

This is achieved via the G-protein system, which is discussed below. 

Figure 12.23 Comparison of the G-protein cycle and the phosphorylase interconversion cycle. The comparison should help to explain the principle underlying the concept of the interconversion cycle and to understand more readilly the G-protein system.

Opiate receptors are linked, via the G-protein system, to K+ ion channels and to voltage-gated Ca " ion channels. Binding of the opiates results in opening of ion channels and hyperpolarisation, so that it is more difficult to initiate an action potential, i.e. they behave like inhibitory neurotransmitters (see above). The binding also results in inhibition of the opening of the Ca ion channels in response to depolarisation. That is, both effects are inhibitory on the nervous activity in the brain, which may explain their analgesic effects. 

Later, in order to account for the effects of a point mutation on the activity of the p2-adrenergic receptor, Samama et al. [29] have proposed an extended version of the ternary complex model. In this model the receptor molecule exists in an equilibrium between the inactive R and the active R conformations. In the absence of ligand, the ability of the receptor to spontaneously convert from the inactive to the active conformation is determined by the isomerization constant, J. The active R conformation is the molecular species that enters into productive interaction with the G protein, described by the equilibrium constant M. The values of both J and M are dependent only on the receptor-G protein system, and are independent of the presence or absence of ligand. The ability of different ligands to perturb this equilibrium is gauged by the ligand-specific equilibrium constant (5, the... 

Other evidence of interaction of insulin with the G-protein system comes from evidence that in rats made diabetic with either streptozotocin or alloxan, functional Gj activity, in liver, appeared to disappear. The use of a specific antibody to quantitate Gj showed that the level of Gj in liver plasma membranes had fallen to below 10% of that of normal animals [114]. The loss of this key G-protein may explain some of the hormonal and other abnormalities seen in diabetes. 

Besides these effects of AlF, on G protein systems, aluminum has its own actions on the phosphoinositide signaling pathway. Aluminum specifically inhibits the Ca2+-dependent enzyme phospholipase C which acts on PIP2. It was found that aluminum chloride inhibited the hydrolysis of PIP2 in a concentration-dependent manner with an IC(50) slightly above 100 pM [56]. The inhibition observed is competitive in nature with the substrate PIP2 [57]. 

The transition temperatures of carbohydrates and proteins are significantly affected by water. It is often reported that an increase in water content results in a substantial decrease in transition temperatures (Slade and Levine 1995). For example, the glass transition of dehydrated food solids decreases as a result of water sorption (i.e., water uptake from its surroundings) and their properties may change from those of the glassy solid to viscous liquids or syrup (e.g., sugar systems) or leathery material (e.g., protein systems) in an isothermal process. 

Recent work has been conducted to examine sweetener recognition by identifying the receptor molecules in the sweet taste receptor cells biochemically and physiologically. It is thought that intense sweeteners react with membrane receptor proteins connected to a G protein system... 

Walker, J. and Barrett, J. (1993) Evidence for a G protein system in the tegumental brush border plasma membrane of Hymenolepis diminuta. Int. J. Parasitol. 23 281-284. 

It would appear that in in vitro systems AlFx interferes with the functioning of many, but not all, G-protein systems. Adenylate cyclase stimulation was first reported in an in vitro system (Sternweis and Gilman 1982). In hepatocytes, AlFx causes a rise in intracellular Ca, suggesting that the G protein activated is coupled to phospholipase C-dependent phosphatidyl inositide hydrolysis (Blackmore et al. 1985), which appears to be the case in a number of cell types, e.g., parotid cells (Mertz et al. 1990). AlFx is reported to activate many other isolated G proteins, such as the G protein that activates channels in guinea pig atrial cells (Yatani and Brown 1991), that do not interact with either adenyl cyclase or the phosphatidyl inositide pathway. 

More recently, Huang and Bittar (1991) found that GTP chelation of A1 stopped GTP stimulating the G-protein system that activates Na efflux in barnacle fibers. 

Miller et al. (1989) proposed that even if A1 and AIF both inhibit GTP hydrolysis, they could have opposite effects on the G-protein system, as he had seen in his experiments. In an attempt to reconcile his own data with those of Martin, Miller argued that, while Al was also seen to inhibit GTP hydrolysis in the GTP-transducin system that he used, the primary effect must be to slow GTP replacement of GDP on the G protein and thus inhibit the action of the G protein. Secondarily, Al replacement of Mg could inhibit GTP hydrolysis on the G protein. Miller did not consider an alternative possibility, that the GTP-Al interaction varies with Al concentration and/or free Mg so that the Al-GTP effect is biphasic, activating at low levels of Al that inhibit hydrolysis and inhibiting at levels that inhibit GTP/GDP exchange. Alternatively, the interaction of Al-GTP with one G protein may have a predominant effect on GTP/GDP exchange, while interaction with another could result predominantly in slowing hydrolysis. 

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