Elevation of cytosolic

TABLE 5.11 Agents Causing Sustained Elevation of Cytosolic Ca and/or Impaired Synthesis of ATP... 

Group II assays consist of those monitoring cellular second messengers. Thus, activation of receptors to cause Gs-protein activation of adenylate cyclase will lead to elevation of cytosolic or extracellularly secreted cyclic AMP. This second messenger phosphorylates numerous cyclic AMP-dependent protein kinases, which go on to phosphorylate metabolic enzymes and transport and regulatory proteins (see Chapter 2). Cyclic AMP can be detected either radiometrically or with fluorescent probe technology. 

If some of the electrophysiological effects of oxidant stress occur secondary to an elevation in intracellular calcium, it is important to consider the possible factors that may underlie the initial elevation of calcium. In the simplest analysis, elevation of cytosolic calcium may be due to (1) redistribution of intracellular calcium stores (2) increased calcium influx or (3) decreased calcium efflux. 

In spite of having no intrinsic catalytic domains, activation of T lymphocytes commences with tyrosine phosphorylations, activation of PLC-v with production of IP3 and DAG, and elevation of cytosolic free Ca2+. Thus, the consequences of receptor ligation are not dissimilar from those induced by the receptors for EGF or PDGF. An early study trying to explain the induction of tyrosine kinase activity resulted in the discovery of the nonreceptor protein tyrosine kinase Lck (p56lck), a T-cell-specific member of the Src family. Lck is associated with the cytosolic tail of CD4 (in helper T cells) or CD8 (in cytotoxic T cells) (Figure 8.14). As mentioned, the extracellular domains of these... 

Correct answer = D. Ca2+ released from the sarcoplasmic reticulum during exercise binds to the calmodulin subunit of phosphorylase kinase, thereby activating this enzyme. The other choices are not caused by an elevation of cytosolic calcium. 

All in all, cell injury almost invariably results in generation of pathological Ca2+ signals, which usually appear in a form of prolonged elevations of cytosolic Ca2+ concentration. These pathological Ca2+ signals originate from increased plasmalemmal Ca2+entry, increased Ca2+ release, compromised Ca2+ extrusion or... 

Nicotera P., Hartzell P., Baldi C., Svensson S.A., Bellomo G., and Orrenius S. 1986 Cystamine induces toxicity in hepatocytes through the elevation of cytosolic Ca2+ and the stimulation of a nonlysosomal proteolytic system. J Biol Chem 261, 14628-14635. 

In common with other cellular systems, refilling of Ca2+ stores following their release appears to depend upon a thapsigargin-sensitive Ca2+-ATPase. Furthermore, such store depletion appears to induce a capacitative Ca2+ influx. Thus, the Ca2+-ATPase inhibitor thapsigargin produced the expected elevation of cytosolic [Ca2+] in osteoclasts studied in Ca2+-free extracellular solutions. Restoration of the extracellular [Ca2+] then produced a cytosolic [Ca2+] overshoot. Similar effects followed Ca2+ store depletion by ionomycin in cells bathed in EGTA-containing solutions when extracellular [Ca2+] was similarly restored. Both studies suggested capacitative Ca2+ influx processes from the extracellular space by a cytosolic route (Shankar et al., 1994). 

Zaidi M, MacIntyre I, Datta, H. 1990. Intracellular calcium in the control of osteoclast function. II. Paradoxical elevation of cytosolic free calcium by verapamil. Biochem Biophys Res Commun 167 807-12. 

Ginsenoside Rgi had no effect on arachidonate metabolism, but it did reduce the elevation of cytosolic free calcium concentration [Ca2+]i shown in the second phase (Ca2+ influx) induced by adrenaline and thrombin "Fig. (37)". The results suggest that ginsenoside Rgl in red ginseng roots may be effective as a drug for the treatment of arteriosclerosis and thrombosis. 

The role of gastrin and cholecystokinin in tumors of gastrointestinal tract is reported by Lamers and Jansen [53]. Elevation of cytosolic calcium in SCLC by cholecystokinin has also been reported [54]. 

Contractile tension is maintained during this sustained period of only modest elevation of cytosolic Ca " by the accompanying processes involving PKC which increase myofilament sensitivity to Ca ". Calcium release from... 

Cytosolic Ca " is transferred into the store by a 105 kDa Ca, Mg -ATPase situated in the sr membrane. This enzyme pump undergoes Ca -dependent phosphorylation (Sumida et /., 1984). It is also regulated through cAMP-mediated phosphorylation of phos-pholamban (Raeymaekers etal., 1986 Eggprmont etal., 1988 Twort and van Breemen, 1989), as a result of which elevation of cytosolic cAMP lowers cytosolic Ca by stimulating uptake into the sr. 

McConkey, D.J., Nicotera, P., Hartzell, P., Bellomo, G., Wyllie, A.H. and Orrenius, S. (1989). Glucocorticoids activate a suicide process in thymocytes through an elevation of cytosolic Ca concentration. Arch. Biochem. Biophys. 269, 365-370. 

Whyte, M.K.B., Meagher, L.C., Hardwick, S.J., Savill, J.S. and Haslett, C. (1993b). Transient elevations of cytosolic free calcium retard subsequent apoptosis in neutrophils in vitro. J. Clin. Invest. 92, 446—455. 

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