Second messengers structure

The intracellular hgand-gated Ca " channels include the channels in endoplasmic and sarcoplasmic reticulum (SR) membranes that are opened upon binding of the second messenger, inositol triphosphate (IP3). These are intracellular Ca release channels that allow Ca to exit from intracellular stores, and consequently to increase the concentration of cytoplasmic Ca [5]. A second type of intracellular Ca release channel is the Ca - and ryanodine-sensitive channel that was originally characterized and isolated from cardiac and skeletal muscle [5-7] but appears to exist in many types of cells. It has become evident that IP3-gated channels and ryanodine-sensitive channels are structurally related but distinct proteins [8] that are present in many cell types [9]. While very interesting, time and space will not allow for further discussion of these channels. 

G proteins regulate intracellular concentrations of second messengers. G proteins control intracellular cAMP concentrations by mediating the ability of neurotransmitters to activate or inhibit adenylyl cyclase. The mechanism by which neurotransmitters stimulate adenylyl cyclase is well known. Activation of those neurotransmitter receptors that couple to Gs results in the generation of free G(IS subunits, which bind to and thus directly activate adenylyl cyclase. In addition, free Py-subunit complexes activate certain subtypes of adenylyl cyclase (see Ch. 21). A similar mechanism appears to be the case for G(IO f, a type of G protein structurally related to G that is enriched in olfactory epithelium and striatum (Ch. 50). 

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. 

Glycerophospholipids are used for membrane synthesis and for producing a hydrophilic surface layer on lipoproteins such as VLDL. In cell membranes, they also serve as a reservoir of second messengers such as diacylglycerol, inositol 1,4,5-triphosphate, and arachidonic acid. Their structure is similar to triglycerides, except that the last fatty acid is replaced by phosphate and a water-soluble group such as choline (phosphatidylcholine, lecithin) or inositol (phosphatidyl-inositol). 

Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins. 

Phospholipase C (PTC, EC 3.1.4.3) catalyzes the hydrolysis of the phosphodiester bond in phospholipids. It releases the second messenger molecule diacylglycerin (DAG) important in the signal transduction cascade and a phosphorylated headgroup . The active site of the enzyme contains three Zn ions with two of them in close proximity. Only few crystal structures are solved until now " . ... 

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