Turnover, endoplasmic reticulum

Fig. 4 Current model for nicotine upregulation of a4p2 nAChRs. a Schematic of a ceU indicating major steps in the lifecycle of a nAChR. Nicotine accumulates within the cell. Within the endoplasmic reticulum, nicotine binds to nAChR subunits to facilitate assembly, or binds at the interface of an aP subunit pair to enhance maturation of a pentameric nAChR (Sallette et al. 2004, 2005). The strong influence of nicotine on maturation of the P2 subunit might also favour a change in nAChR stoichiometry, from (a4)3(P2)2 to (a4)2(P2)3 (Moroni et al. 2006). These actions could result in an increase in the membrane insertion of competent nAChRs. The possibflity of an additional action of nicotine to impede nAChR turnover or degradation is indicated by the dotted line, b Binding of nicotine to the extracellular domain of unassembled nAChR subunits facilitates assembly, c Binding of nicotine at an aP interface facilitates maturation of a pentameric nAChR. Items b and c adapted from Nashmi and Lester (2007), with permission from Elsevier...

Metabolic activation of PAHs consists of an oxidation of the rings of unsubstituted PAHs. These oxidations are carried out by mixed function oxidases of the liver which contain cytochromes P450 and P448 and require reduced nicotine adenine dinucleotide and oxygen. In this oxidation, an epoxide intermediate is formed which has been shown to have the requisite chemical reactivity to bind covalently with DNA and histones and to serve as the ultimate carcinogenic form of PAH. Administration of 3-MC to rats increased hepatic nuclear proteins and caused a turnover of protein of the endoplasmic reticulum. Studies of " C amino acid incorporation showed that 3-MC causes increased protein synthesis and reduced degradation of protein. 

Many oncogenes such as ras, src, sis, fms, and fes enhance cellular PI turnover. Phosphatidyl breakdown by phospholipase C generates two second messengers, diacyIglycerol and inositol trisphosphate. The formed directly activates protein kinase C, and the latter binds to the receptor on endoplasmic reticulum to mobilize calcium ions. Therefore, we screened culture filtrates of microorganisms for inhibitors of PI turnover and thus isolated psi-tectorigenin (Fig. 11, ref. 23). ... 

Proteasomes are the major cytosolic and nuclear protein degradation machineries and they are also responsible for the proteolysis of misfolded, ER-dislocated (endoplasmic reticulum) proteins [1-3]. Proteasomal protein turnover takes place in an ubiquitin-dependent manner. The proteasome-generated products - ohgopeptides varying in length from 3 to up to 30 amino acid residues - are further processed by aminopeptidases. In higher vertebrates, antigenic peptides are selected from the peptide pool produced by proteasomes and downstream aminopeptidases for presentation on the outer cell surface by major histocompatibility class 1 (MHCl) protein complexes. In this way, proteasomes are essential factors in the detection and eradication of virally infected cells. 

Among organelles, microbodies have an unusually short half life 1 to 5 days or about /lo of that of mitochondria. The reasons for the rapid turnover of microbodies are not known. The enzymes found in microbodies are synthesized in the endoplasmic reticulum. The mechanism of transfer of the enzymes from endoplasmic reticulum to microbodies has not been discovered. In view of their rapid turnover, microbodies must constantly be eliminated from the cell. Although entrapment in areas of focal cytoplasmic degradation is certainly involved, it appears that other still unknown mechanisms of degradation exist. 

After the induction of endoplasmic reticulum membranes and enzymes, enzymes and membranes disappear when the inductive stimulus is withdrawn. The enzyme disappears faster than the membrane, but focal cytoplasmic degradation does not develop, suggesting that the lysosomal hydrolases are not likely to be involved in discrete turnover of the endoplasmic reticulum [80]. 

Fig. 1. Stimulus-induced turnover of phosphatidylinositol 4,5-bisphosphate (PIPo) and the role of turnover products in signal transduction. PI, phosphatidylinositol PIP, phosphatidylinositol 4-phosphate PIPo, phosphatidylinositol 4,5 bisphosphate IP, inositol trisphosphate IP, inositol tetrakisphosphate IPo inositol bisphosphate IP, inositol monophosphate ER, endoplasmic reticulum DG, diacylglycerol MG, monoglyceride AA, arachidonic acid PA, phosphatidic acid. [Adapted from 38]...

A model depicting turnover and biosynthesis of the H,K ATPase is shown in the figure. The two subunits of the ATPase are synthesized and coassembled in the endoplasmic reticulum and proceed to the trans-Golgi. From there, tubules are budded off. The turnover of the protein in the cytoplasmic tubules is relatively slow compared to when the protein is present in the membrane of the secretory canaliculus, where it is subject to endocytosis. On the right is shown the synthesis of the two subunits followed by processing in the Golgi. The mature pump subunits are inserted into the tubulovesicles. Stimulation of add secretion by histamine or acetylcholine results in rapid movement to the secretory canaliculus (t 2 = 5 minutes). Return from the canaliculus to the tubulovesicles has a t 2 of 60 minutes. The half-life of the pump protein is approximately 50 hours. 

A stimulus which alters the steady-state level of an endogenous cellular component may do so by influencing its rate of synthesis, its rate of break-down, or both. When administered to intact animals, phenobarbital or 3-methylcholanthrene increase (20-50%) the steady-state level of microsomal protein. Similarly, micro-somes from animals pretreated with phenobarbital or 3-methylcholanthrene incorporate radioactive amino acids into protein more rapidly than microsomes from control animals and this effect is blocked by co-administration of actinomycin-D. It was therefore assumed that the increased levels of microsomal protein and enzyme activity after inducers were the result of enhanced synthesis. However, turnover studies have revealed that phenobarbital in particular has a profound effect upon microsomal protein catabolism. Proteins of the endoplasmic reticulum were labelled by injection of radioactive amino acids and the rate at which radioactivity disappeared from the microsomes was compared in control and phenobarbital-treated animals. Assuming a comparable degree of isotope re-utilization in the two groups, this approach provides a relative measure of microsomal-protein turnover. In control animals, radioactivity of total microsomal protein decreases with time with a half-time of about 3 days. In phenobarbital-treated animals, however, there is a marked stabilization of microsomal protein so that almost no radioactivity is lost over a S-day period. The reduced protein catabolism is observed both in total microsomes and in a purified microsomal protein, NADPH cytochrome c reductase. Thus, repeated administration of phenobarbital to animals evokes an increase in... 

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