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Striated MusclesSkeletal and Cardiac Muscles
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Relaxation occurs when calcium concentration is lowered by the actions of Ca-ATPase on the longitudinal part of the sarcoplasmic reticulum. A protein called phospholamban normally inhibits sarcoplasmic reticulum Ca-ATPase, but when it is phosphorylated, it exerts less inhibition, so calcium uptake is enhanced. Calsequestrin present in the cytosol of cardiac muscle cells serves as a sink for calcium. In addition to the Ca-ATPase in the sarcolemma, the Na+/Ca++ exchanger pumps calcium out of the cell. The Na+/Ca++ exchanger operates on the basis of sodium ion gradient. Three sodium ions enter for every one calcium ion leaving the cell via the exchanger.
Genetically Determined Ventricular Arrhythmias
Published in Andrea Natale, Oussama M. Wazni, Kalyanam Shivkumar, Francis E. Marchlinski, Handbook of Cardiac Electrophysiology, 2020
Houman Khakpour, Jason S. Bradfield
Two variants of CPVT have been described based on their genetic mutation and mode of transmission. CPVT1 has a mutation in the ryanodine 2 receptor gene (RyR2) which leads to delayed afterdepolarization (DAD)-induced extrasystolic activity from defective calcium handling. The resulting transmural dispersion of repolarization provides the substrate for the development of re-entrant tachyarrhythmias.13,76 The RyR2 gene shows autosomal dominant inheritance. CPVT2 is defined by a mutation in the calsequestrin (CASQ2) gene and has an autosomal recessive inheritance. Other unidentified genes are also believed to result in CPVT. The ryanodine receptor is located on the sarcoplasmic reticulum and allows the release of calcium into the cell, thus facilitating excitation contraction coupling in the myocardium. Calsequestrin gene mutations interfere with sarcoplasmic calcium storage.13
Nerve-to-Muscle Signals
Published in Peter W. Hochachka, Muscles as Molecular and Metabolic Machines, 2019
In addition to the above, fast and slow muscle activation may be influenced by the amount and kind of calsequestrin found in the jSR. Calsequestrin, a protein discovered by McLennan and Wong in 1971, is a sink for Ca++ in the terminal cisternae. It can bind up to 40 mmol Ca++ mol calsequestrin and appears to be positioned just below the “Toot proteins”. Thus, it is in a good position for transferring its Ca++ (relatively) directly to the SR Ca++ release channel whenever the latter is activated. The degree to which the calsequestrin-foot protein interaction speeds up Ca++ flux is not known. However, it is known that calsequestrin occurs in two isoforms, as two distinct gene products. One calsequestrin gene is active in cardiac (and slow-twitch) muscle, while the other is active in fast-twitch muscle. Interestingly, as mentioned above, the same is true also for the foot proteins, which also occur as tissue-specific isoforms.
Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure
Published in Expert Opinion on Therapeutic Targets, 2020
Patrick Connell, Tarah A. Word, Xander H. T. Wehrens
Another proposed theory is that mutations in RyR2 result in weakened binding between the N-terminal and central domains of the protein, resulting in conformational changes, destabilizing the closed state of the channel, eventually leading to Ca2+ leak, a process known as domain unzipping [29]. A third proposed mechanism for DADs and triggered activity in CPVT is that Ca2+ accumulation in the SR stimulates spontaneous SR Ca2+ release, a process known as store-overload induced-Ca2+ release [30]. As Ca2+ handling is altered in CPVT, Ca2+ sensing by RyR2 may be impacted on both the cytosolic and luminal side of the channel, with work supporting the role of cardiac calsequestrin (Casq2) in luminal Ca2+ sensing and handling [31,32].
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
Another modulator of cytosolic calcium concentration is calsequestrin, which binds calcium within the sarcoplasmic reticulum. Intraperitoneal injection of WT-CASQ2 into knockout mice normalized levels of calsequestrin and its associated proteins, and significantly suppressed catecholaminergic arrhythmias [92]. A follow-up study demonstrated that the curative effects were seen for one year after a single vector injection [93]. Lodola et al. found that administration of human CASQ gene resulted in a decrease in after depolarizations [106]. A more recent study used both CASQ2 knockout mouse models and subjects with D307H mutations, which causes polymorphic VT in humans. The mice were treated with intracardial or intraperitoneal adenoviruses containing the CASQ gene. Subjects expressing >33% of the normal CASQ2 level did not develop arrhythmias, but even mice with lower levels were protected against sustained VT [94].
Detection of Proteins Associated with Extracellular Matrix Regulation in the Aqueous Humour of Patients with Primary Glaucoma
Published in Current Eye Research, 2019
Sampath Nikhalashree, Ronnie George, Balekudaru Shantha, Vijaya Lingam, Wadke Vidya, Manish Panday, Konerirajapuram Natarajan Sulochana, Karunakaran Coral
There were few unique sets of proteins identified in our study that were not reported earlier in AH studies and they include, afadin, an actin filament-binding and a neuronal intercellular adhesion protein, known to interact with Nectin 3. They also interact with JAG1 involved in the differentiation of rat lens development.37 Syntabulin, also known as golsyn (human Golgi-localized syntaphilin-related protein) functions as a vesicular transporter in mice brain, and this gene is mapped to human chromosome 8q23, the loci responsible for primary open-angle glaucoma.38 Calsequestrin and sarcalumenin are calcium-binding proteins, and they might play a role in neurodegeneration based on calcium-dependent mechanism.39