Calcium pumps

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

The trigger for all musele eontraetion is an increase in Ca eoneentration in the vicinity of the muscle fibers of skeletal muscle or the myocytes of cardiac and smooth muscle. In all these cases, this increase in Ca is due to the flow of Ca through calcium channels (Figure 17.24). A muscle contraction ends when the Ca concentration is reduced by specific calcium pumps (such as the SR Ca -ATPase, Chapter 10). The sarcoplasmic reticulum, t-tubule, and sarcolemmal membranes all contain Ca channels. As we shall see, the Ca channels of the SR function together with the t-tubules in a remarkable coupled process. 

Site symmetry symbols, I, 128 Six-coordinate compounds stereochemistry, 1, 49-69 Six-membered rings metal complexes, 2, 79 Skeletal muscle sarcoplasmic reticulum calcium pump, 6, 565 Slags... 

Decreased cerebral blood flow, resulting from acute arterial occlusion, reduces oxygen and glucose delivery to brain tissue with subsequent lactic acid production, blood-brain barrier breakdown, inflammation, sodium and calcium pump dysfunction, glutamate release, intracellular calcium influx, free-radical generation, and finally membrane and nucleic acid breakdown and cell death. The degree of cerebral blood flow reduction following arterial occlusion is not uniform. Tissue at the... 

In addition to the Na/Ca exchange mechanism, the sar-colemma also contains a CaATPase that removes calcium from the cytosol. This calcium pump plays only a small role in the extrusion of calcium from the cell during normal activity (Bers, 1991 Barry and Bridge, 1993). However, Kaneko et al. (1989), have shown that the activity of the CaATPase may be inhibited by free radicals and thus the ability of the cell to extrude calcium in the presence of a maintained oxidant stress may be further compromised (Kaneko et al., 1989). 

Figure 8 Localization of solute (propranolol) within the lipid bilayer. This solute-membrane interaction has been shown to influence the conformation and activity of a calcium-pump protein (X) embedded in the bilayer. (From Ref. 78.)... 

On the other hand, microsomes may also directly oxidize or reduce various substrates. As already mentioned, microsomal oxidation of carbon tetrachloride results in the formation of trichloromethyl free radical and the initiation of lipid peroxidation. The effect of carbon tetrachloride on microsomes has been widely studied in connection with its cytotoxic activity in humans and animals. It has been shown that CCI4 is reduced by cytochrome P-450. For example, by the use of spin-trapping technique, Albani et al. [38] demonstrated the formation of the CCI3 radical in rat liver microsomal fractions and in vivo in rats. McCay et al. [39] found that carbon tetrachloride metabolism to CC13 by rat liver accompanied by the formation of lipid dienyl and lipid peroxydienyl radicals. The incubation of carbon tetrachloride with liver cells resulted in the formation of the C02 free radical (identified as the PBN-CO2 radical spin adduct) in addition to trichoromethyl radical [40]. It was found that glutathione rather than dioxygen is needed for the formation of this additional free radical. The formation of trichloromethyl radical caused the inactivation of hepatic microsomal calcium pump [41]. 

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... 

The sodium and calcium pumps can be isolated to near purity and still exhibit most of the biochemical properties of the native pump. Some kinetic properties of these pumps in native membranes are altered or disappear as membrane preparations are purified. For example, when measured in intact membranes, the time-dependencies of phosphorylation and dephosphorylation of the pump catalytic sites exhibit biphasic fast to slow rate transition this characteristic progressively disappears as the membranes are treated with mild detergents. One suggested explanation is that, as the pumps begin to cycle, the catalytic subunits associate into higher oligomers that may permit more efficient transfer of the energy from ATP into the ion transport process [29, 30], Some structural evidence indicates that Na,K pumps exist in cell membranes as multimers of (a 3)2 [31]. 

FIGURE 22-3 Structures of compounds that inhibit sarcoendoplas-mic reticulum Ca2+-ATPase (SERCA) calcium pumps. 

Raeymaekers L, Wuytack F 1996 Calcium Pumps. In Barany M (ed) Biochemistry of smooth muscle contraction. Academic Press, New York, p 241-253 Shull GE 2000 Gene knockout studies of Ca2+-transporting ATPases. Eur J Biochem 267 5284-5290... 

Mehorta BD, Moorthy KS, Ravichandra R, et al. 1989. Effects of cyclodiene compounds on calcium pump activity in rat brain and heart. Toxicology 54 17-29. 

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. 

Axelband F, Assungao-Miranda I, de Paula IR, Ferrao FM, Dias J, Miranda A, Miranda F, Lara LS, Vieyra A. (2009) Ang-(3 ) suppresses inhibition of renal plasma membrane calcium pump by Ang II. Regul Pept 155 81-90. 

Garcia M, Gonzalez R. 1985. Uncoupling of the calcium pump of the sarcoplasmic reticulum by kerosene. Toxicol Lett 28(l) 59-64. 

Upon binding calcium ions, the small acidic protein known as calmodulin can activate enzymes by binding to a wide variety of proteins containing cahnodulin-binding domains. Such proteins include cAMP phosphodiesterase, calmodulin-dependent nitric oxide synthase, calmodulin kinases, the plasma membrane calcium pump, calcineurin, and calmodulin-dependent inositol-(l,4,5)-trisphosphate 3-kinase. See also Activation Autoinhibition... 

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