Endoplasmic reticulum, calcium pumps

The smooth endoplasmic reticulum calcium pumps (SERCA) found in brain were first identified in sarcoplasmic reticulum. The three isoforms of SERCA are products of separate genes SERCA-1 is expressed in fast-twitch skeletal muscle SERCA-2a in cardiac/slow-twitch muscle SERCA-2b, an alternatively spliced form, is expressed in smooth muscle and non-muscle tissues SERCA-3 is... 

Long RM, Moore L. 1986b. Inhibition of liver endoplasmic reticulum calcium pump by CCH and release of a sequestered calcium pool. Biochem Pharmacol 35 4131-4137. 

Waldron, R. T., Short, A. D., Meadows, J. J., Ghosh, T. K. and Gill, D. L., 1994, Endoplasmic reticulum calcium pump expression and control of cell growth. J Biol Chem 269, 11927—33. 

Calcium ions (Ca ) are important for the mediation of hepatic injury. Cytosolic free calcium is maintained at relatively low concentrations compared to the extracellular levels. The majority of intracellular calcium is sequestered within the mitochondria and endoplasmic reticulum. Membrane associated calcium and magnesium ATPases are responsible for maintaining the calcium gradient (Farrell et ah, 1990). Significant and persistent increases in the intracellular calcium result from nonspecific increases in permeability of the plasma membrane, mitochondrial membranes, and membranes of the smooth endoplasmic reticulum. Calcium pumps in the mitochondrial membrane require NADPH, thus depletion of available NADPH can cause calcium release from mitochondria (Cullen, 2005). 

The cytosolic concentration of free Ca2+ is generally at or below 100 mi, far lower than that in the surrounding medium, whether pond water or blood plasma. The ubiquitous occurrence of inorganic phosphates (Pj and I l ,) at millimolar concentrations in the cytosol necessitates a low cytosolic Ca2+ concentration, because inorganic phosphate combines with calcium to form relatively insoluble calcium phosphates. Calcium ions are pumped out of the cytosol by a P-type ATPase, the plasma membrane Ca2+ pump. Another P-type Ca2+ pump in the endoplasmic reticulum moves Ca2+ into the ER lumen, a compartment separate from the cytosol. In myocytes, Ca2+ is normally sequestered in a specialized form of endoplasmic reticulum called the sarcoplasmic reticulum. The sarcoplasmic and endoplasmic reticulum calcium (SERCA) pumps are closely related in structure and mechanism, and both are inhibited by the tumor-promoting agent thapsigargin, which does not affect the plasma membrane Ca2+ pump. 

Chami, M., Gozuacik, D., Lagorce, D., Brini, M., Faison, P., Peaucellier, G., Pinton, P., Lecoeur, H., Gougeon, M. L., le Maire, M., Rizzuto, R., Brechot, C. and Paterlini-Brechot, P., 2001, SERCA1 truncated proteins unable to pump calcium reduce the endoplasmic reticulum calcium concentration and induce apoptosis. J Cell Biol 153, 1301-14. 

Schmidt, T., Zaib, F., Samson, S.E., Kwan, C.Y., and Grover, A.K. 2004. Peroxynitrite resistance of sarco/endoplasmic reticulum Ca2+ pump in pig coronary artery endothelium and smooth muscle. Cell Calcium 36 77-82. 

The deterministic dynamics of this cluster model has been investigated in [32, 33]. In addition to IP3 mediated Ca liberation, we considered sarco-endoplasmic reticulum calcium ATPase (SERCA) pumps, which transport Ca from the cytosol to the ER, and a leak flux. The stationary Ca concentration profile that results from these three fluxes is... 

Similarly, each molecule of IP will continue to keep the endoplasmic reticulum calcium channel open until it is phosphorylated to inactive inositol tetrakisphosphate, thus maintaining a flow of calcium ions into the cytosol. Each molecule of calcium-calmodulin will bind to, and activate, a molecule of protein kinase for as long as the cytosol calcium concentration remains high. It is only as the calcium is pumped back into the endoplasmic reticulum that the calcium concentration falls low enough for calmodulin to lose its bound calcium and be inactivated. Again each molecule of phosphorylated enzyme will catalyse the metabolism of many thousands of mol of substrate per second, until it is dephosphorylated by phosphoprotein phosphatase. 

Calcium is pumped out of the cytosol by Ca2+ pumps in the plasma membrane, endoplasmic reticulum, or mitochondria. 

The endoplasmic reticulum (ER) is responsible for the production of the protein and lipid components of most of the cell s organelles. The ER contains a large number of folds, but the membrane forms a single sheet enclosing a single closed sac. This internal space is called the ER lumen. The smooth endoplasmic reticulum (ER) in muscle cells contains the vesicles and tubules that serve as a store of calcium ions. These are released as one step in the muscle contraction process. Calcium pumps, Ca +-ATPases, serve to move the calcium from the cytoplasm to the ER or SR lumen. 

Figure 6.12 The cellular toxicity of TBT caused by damage to the thiols of the Ca2+ pump. This leads to dramatic mobilization of calcium from the ER. The filled circles represent ATP-dependent Ca2+ transporters. Abbreviations TBT, tri-n-butyltin chloride ER, endoplasmic reticulum.

Meanwhile, the polar IP3 moiety binds to intracellular receptors on the endoplasmic reticulum, resulting in the liberation of calcium into the cytosol. The calcium binds to calmodulin, which then activates another group of protein kinases (the Ca2+/CaM-dependent protein kinases). Hormonal stimulation can be short-lived because IP3 and DG are rapidly degraded to inactive forms that are ultimately recycled to PIP2 Ca2+ is pumped back into the endoplasmic reticulum, where it is sequestered. 

Lytton, J., Westlin, M., and Hanley, M. R., 1991, Ihapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem, 266 17067-71. 

Sorin, A., Rosas, G., and Rao, R., 1997, PMR1, a Ca2+-ATPase in yeast Golgi, has properties distinct from sarco/endoplasmic reticulum and plasma membrane calcium pumps. J. Biol. Chem. 272, 9895-9901... 

Papp, B Enyedi, A., Paszty, K., Kov4cs, T., Sarkadi, B., G dos, G., Magnier, C Wuytack, F., Enouf, J. (1992). Simultaneous presence of two distinct endoplasmic-reticulum-type calcium-pump isoforms in human cells. Biochem. J. 288,297-302. 

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