Sarcoplasmic/endoplasmic reticulum

Sarcoplasmic reticulum (SR) is a form of the smoothfaced endoplasmic reticulum (ER) in muscles. It functions as an intracellular Ca2+ store for muscle contraction. Ca2+ is energetically sequestered into the SR by Ca2+-pump/sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA) and released via Ca2+ release channels on stimuli (ryanodine receptor in striated muscles and inositol 1,4,5-trisphosphate receptor in most smooth muscles). Endoplasmic reticulum in non-muscle tissues also functions as an intracellular Ca2+ store. 

Dhitavat, J., Dode, L., Leslie, N., Sakuntabhai, A., Lorette, G., and Hovnanian, A., 2003b, Mutations in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase isoform cause Darier s disease. J Invest Dermatol, 121 486—9. 

Li, Y., Ge, M., Ciani, L., Kuriakose, G., Westover, E.J., Dura, M., Covey, D.F., Freed, J.H., Maxfield, F.R., Lytton, J., and Tabas, I., 2004, Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages../. Biol. Chem. 279, 37030—37039 Lin, P., Yao, Y., Hofmeister, R., Tsien, R.Y., and Farquhar, M.G., 1999, Overexpression of CALNUC (nucleobindin) increases agonist and thapsigargin releasable Ca2+ storage in the Golgi. J. Cell Biol. 145, 279-289... 

The mechanism of action for such peroxidic compounds involves a reductive activation by iron in haem, released as a result of hemoglobin digestion by Plasmodium. This irreversible redox reaction affords carbon-centered free radicals causing the alkylation of haem and of proteins. One such protein (the sarcoplasmic-endoplasmic reticulum ATPase PfATP6) appears to be critical for parasite survival, and there is no indication for resistance by the parasite. However, treatment is expensive and recrudescence of malaria occurs often. Moreover, it was found that at high doses such compounds are neurotoxic. 

The artemisinins appear to kill the parasite by a free radical mechanism—not by the generation of ROS but, rather, by virtue of a free radical associated with the endoperoxide, possibly involving a carbon radical. Evidence points toward activation of the endoperoxide via an iron-dependent mechanism. The resulting free radical selectively targets sarcoplasmic/endoplasmic reticulum Ca " -ATPase of the Plasmodium falciparum (PfATP6), altering calcium stores (49). The artemisinins actually may form covalent adducts to specific membrane-associated proteins after concentrating in infected erythrocytes. 

Ryanodine receptors (RyR) mediate the release of calcium from intracellular stores of the sarcoplasmic/endoplasmic reticulum (SR/ER) following a small calcium influx via voltage-gated calcium channels of the cytoplasmic membrane after depolarization. The process, referred to as calcium-induced calcium release, triggers muscle contraction after electrical excitation in mammalian cardiac as well as in insect striated muscles (I). Three RyR isoforms exist in mammals Type 1, which is predominantly expressed in skeletal muscles Type 2, which is expressed in cardiac muscle and the more ubiquitously expressed Type 3 2 . 

Li Y, Ge M, Ciani L et al. (2004) Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium AT-Pase-2b activity in parallel with increased order of membrane lipids implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages. J Biol Chem 279, 37030-37039. 

Ryanodine receptor (RyR) is an intracellular Ca2+ release channel in the sarcoplasmic reticulum (SR) or the endoplasmic reticulum (ER). RyR binds ryanodine (a plant alkaloid, see Drugs) with a high affinity, after which it is named. 

In the sarcoplasm of smooth muscle cells there is a membrane bound compartment usually referred to as the SR by analogy with skeletal muscle. However, it is not at all clear that the interior of these membrane-bound regions are continuous as they are in skeletal muscle. The primary properties of this system seem to be quite similar to those of the endoplasmic reticulum of many other cell types. In general, calcium is concentrated into the membrane-bound reticulum and then released to initiate the characteristic action of the cell. 

Most living cells, including muscle, maintain the cytoplasmic Ca concentration at submicromolar levels, against steep gradients of [Ca ], both at the cell surface and across the endoplasmic reticulum membrane [17]. In the musele cell two membrane systems are primarily involved in this function the sarcoplasmic reticulum and the surface membrane. 

This chapter will summarize recent developments on the structure of the Ca -ATPase of the sarcoplasmic reticulum with occasional references to the Ca -ATPases in the plasma membranes and endoplasmic reticulum of non-muscle cells. 

Our discussion here will concentrate on the various forms of the Ca " transport ATPases that occur in the sarcoplasmic reticulum of muscle cells of diverse fiber types and in the endoplasmic reticulum of nonmuscle cells (SERCA). The structure of these enzymes will be compared with the Ca transport ATPases of surface membranes (PMCA) [3,29-32,34] and with other ATP-dependent ion pumps that transport Na, K, andH [46,50-52]. 

It is well recognized that is an important regulatory element for many cellular processes, and that the major entry pathway for Ca in many cell types is via plasma membrane Ca channels. Ca channels are functional pores in membranes. They exist in plasma membranes, transverse tubule membranes and in intracellular membranes such as the sarcoplasmic and endoplasmic reticulum. Ca channels are normally closed when opened, Ca passively flows through the chan-... 

In tissue culture, astrocytes, hippocampal neurons and arterial myocytes all express al diffusely in their plas-malemma. In contrast, immunocytochemically stained a2 in astroglia and a3 in myocytes and neurons display reticular patterns and colocalize with the Na+/Ca2+ exchanger (NCX) (Fig. 5-6). These plasmalemma reticular patterns coincide with the patterns of staining for junctional complexes on sarcoplasmic reticulum and, in astroglia and neurons, junctional complexes on endoplasmic reticulum [23]. 

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... 

Raeymaekers L, Verbist J, Wuytack F, Plessers L, Casteels R 1993 Expression of Ca2+ binding proteins of the sarcoplasmic reticulum of striated muscle in the endoplasmic reticulum of pig smooth muscles. Cell Calcium 14 581-589... 

Afonso A, Hunt P, Cheesman S, Alves AC, Cunha CV, do Rosario V, Cravo P. (2006) Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (encoding the sarcoplasmic and endoplasmic reticulum Ca " ATPase), tctp, mdrl, and cglO. Antimicrob Agents Chemother 50 480 89. 

Mobilization of from the stores of the endoplasmic reticulum takes place with the help of channels, of which two types stand out the InsPj receptors and the ryanodin receptors. Both are ligand-gated Ca channels (review Berridge, 1993 see also Chapter 16), in which receptor and ion channel form a structural unit. Tlie InsPs receptors and ryanodin receptors are localized in the endoplasmic and sarcoplasmic reticulum, respectively, and may be opened during the process of signal transduction (Fig. 6.7). 

This general theory is sometimes made more precise by considering that the Golgi body is involved in producing the matrix material while the endoplasmic reticulum transfers calcium to the developing vesicle. The endoplasmic reticulum has been studied most intensively in muscle where its ability to transport calcium into vesicles of the sarcoplasmic reticulum is well known. There is, however, some doubt as to how this ability is developed in non-contractile cells627. ... 

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. 

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. 

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