Local Anesthetics
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
The LA injection causes toxicity resulting in trauma because of: (1) the injected volume; (2) the pressure of injection, and (3) chemically by varying intracellular concentrations of calcium (Nair, 2017). Regarding the later, increased free cytosolic Ca2+ concentration seems to be the primary cause. The mechanism of myotoxicity caused by LAs remains uncertain but it seems that multiple mechanisms are involved. Thus, LAs can bind and activate the ryanodine receptors (RyR) located in the sarcoplasmic reticulum membrane releasing more calcium from the SR to the cytosol and therefore leading to muscle contraction. Nevertheless, activation of the RyRs by LAs is both concentration- and pH-dependent. In fact, the charged form of the LA is the one able to activate the RyR. Inhibition of the ATPase responsible of the calcium reuptake into the SR (SERCA) by LAs also seems to contribute the disturbance of the calcium cellular homeostasis (Dippenaar, 2007). Two of the LAs with myotoxic properties are bupivacaine and ropivacaine, being the former more myotoxic than the latter. The probable reason for this difference in myotoxicity seems to be the higher liposolubility of bupivacaine compared with ropivacaine.
Artemisinins
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
An alternate hypothesis for the mechanism of action of the artemisinins proposes a role for artemisinin interfering with calcium homeostasis in the parasite cytoplasm (Krishna et al., 2006). Homologs of the sarcoplasmic-endoplasmic reticulum Ca2+−adenosine triphosphatases (ATPases) (SERCA) have been identified in P. falciparum (Kimura et al., 1993) and are expressed at different stages of the life cycle (Krishna et al., 2001b). When expressed in Xenopus oocytes, PfATP6 is inhibited by artemisinins but not by other antimalarials (Eckstein-Ludwig et al., 2003). Furthermore, thapsigargin, which shares chemical similarities with artemisinin, is a potent and selective inhibitor of SERCA. In cross-competition studies, thapsigargin demonstrates antagonistic antiparasitic activity with artemisinin, consistent with a common mode of action (Eckstein-Ludwig et al., 2003). However, more recent work contradicted the notion of SERCA inhibition, and no antagonism between thapsigargin and artemisinin was reported (del Pilar Crespo et al., 2008).
AGE-RAGE Axis in the Aging and Diabetic Heart
Sara C. Zapico in Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Impaired calcium homeostasis is a hallmark of diabetes and heart failure. The tight regulation of calcium transients during systole and diastole is directly responsible for regulating contraction and relaxation of the contractile apparatus in cardiomyocytes. For a more detailed review of the role of calcium in the heart and the progression to heart failure, the reader is referred to (Gorski et al. 2015). Depolarization of the sarcolemma triggers the L-type caclium channels to allow entry of a small amount of extracellular calicum into the cytosol. This calcium then binds to RyR on the sarcoplasmic reticulum, prompting the release of stored calcium from the sarcoplasmic reticulum into the cytosol, a process termed calcium-induced calcium release. This results in an approximate 10-fold increase in cytosolic calcium, which can then bind to troponin and induce a conformational change that allows for contraction of the contractile apparatus. In order for relaxation to occur, the calcium must be cleared from the cytosol. This primarily occurs through the activity of the SERCA, which pumps calcium back into the sarcoplasmic reticulum at the cost of ATP. Additionally, the sodium-calcium exchanger (NCX) at the sarcolemma extrudes calcium from the cytosol in exchange for sodium entry into the cytosol.
Cellular Calcium Signals in Cancer Chemoprevention and Chemotherapy by Phytochemicals
Published in Nutrition and Cancer, 2022
Xue Li, Shuhan Miao, Feng Li, Fen Ye, Guang Yue, Rongzhu Lu, Haijun Shen, Yang Ye
Curcumin is a natural phenolic compound obtained from Curcuma longa (106) with multiple activities including anti-proliferation, antioxidant, anti-inflammatory, antiviral and anticancer activities (107, 108). Curcumin causes cell death in different cancers through inducing apoptosis, cell cycle arrest, migration and autophagy (109, 110). Curcumin exerts anticancer effects by regulating calcium signaling in human papillary thyroid carcinoma cancer (111), ovarian cancer (61) and non-small cell lung cancer (112). Seo et al. reported that curcumin increases cytoplasmic Ca2+ concentration to induce apoptosis in ovarian cancer cells. SERCA is an important calcium pump that removes cytosolic Ca2+ to ER calcium stores, which is critical for calcium homeostasis. Curcumin increases cytoplasmic Ca2+ concentration through inhibiting the activity of SERCA with no effects on the expression of SERCA (61). These results indicated that curcumin inhibited SERCA activity to affect calcium homeostasis to prevent tumor growth. In addition, curcumin disrupts calcium homeostasis in human papillary thyroid carcinoma cells via inhibition of SERCA. The increased cytosolic Ca2+ concentration followed by activated calcium/calmodulin-dependent protein kinase II (CaMKII)-JNK signaling pathway and ER stress lead to apoptosis (111). In human non-small cell lung cancer, curcumin caused Ca2+ overload by Bcl-2-mediated IP3R phosphorylation, followed by the activation of cleaved caspase-3 and cleaved caspase-9 and the decrease of MMP and apoptosis (112).
Biological therapies targeting arrhythmias: are cells and genes the answer?
Published in Expert Opinion on Biological Therapy, 2018
Debbie Falconer, Nikolaos Papageorgiou, Emmanuel Androulakis, Yasmin Alfallouji, Wei Yao Lim, Rui Providencia, Dimitris Tousoulis
Sarcoplasmic reticulum Ca-ATPase (SERCA) 2a is an ATPase pump that regulates cytosolic calcium concentration by transferring Ca into the lumen of the sarcoplasmic reticulum. Following ischemia, SERCA activity decreases, increasing cytosolic Ca and triggering afterdepolarizations [7]. SERCA2a was overexpressed in the left ventricles of pigs which had undergone LAD occlusion and reperfusion (Table 2). There was a significant reduction in arrhythmias of transfected animals compared with controls. There was no difference, however, in animals which had undergone artery occlusion but no reperfusion [77]. Deficient SERCA2a is also associated with cardiac failure. When transferred into the failing hearts of rats [78] and guinea pigs [79], ventricular arrhythmias were significantly suppressed. SERCA2a overexpression in the heart of healthy young guinea pigs resulted in a fourfold reduction in alternans-mediated ventricular arrhythmias [80].
Cardiotonic steroids as potential Na+/K+-ATPase inhibitors – a computational study
Published in Journal of Receptors and Signal Transduction, 2019
Chirag N. Patel, Sivakumar Prasanth Kumar, Krunal M. Modi, Mehul N. Soni, Nainesh R. Modi, Himanshu A. Pandya
Na+/K+-ATPase, is a membrane protein, associated in the formation of Na+ and K+ gradients across plasma membranes and in the persistence of cytoplasmic Na+ levels [1]. Three Na+ ions and two K+ ions were pumped by concentrated gradient which has been developed by Na+ pump through inside as well as outside the cell, applying this method the energy achieved by the hydrolysis of a molecule of ATP. Na+/K+-ATPase, urges various aspects of Na+/H+ and Na+/Ca2+ exchangers improving, cell volume, pH and Ca2+ levels [2–4]. Furthermore, signal transduction and cytoskeleton regulation was performed by Na+/K+-ATPase proteins which supervise the osmotic level of cell [5]. It also contributes to the catalytic cycle with specific peculiarities which is ephemeral phosphorylated form which is composition of ATP hydrolysis [1,6]. The cardiac pledges determined by Na+/K+-ATPase by transferring of Na+/Ca2+ exchanger which regulates the combination of intracellular Na+ to resolve the Ca2+ absorption over the Na+/Ca2+ exchange (Figure 1). In addition, sarcoplasmic reticulum (SR) acquires the Ca2+ from SR Ca2+ ATPase (SERCA) which remitted during consecutive exhilaration [7].
Related Knowledge Centers
- Atpase
- Calcium
- Calcium Atpase
- Sarcoplasmic Reticulum
- Endoplasmic Reticulum
- P-Type Atpase
- Muscle Cell
- Cytosol
- Lumen
- Atp Hydrolysis