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Oxidation of Ion Channels in the Aging Process
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
The crucial role of the RyR in the learning process of the hippocampus during aging is now well established as treatments that inhibit the CICR mechanism have a marked effect on rescuing learning defects in aging animals [93,185,187,192]. For example, expression of RyR-accessory subunit calstabin2 (FK506-binding protein 12.6/1b), a homolog of muscle calstabin1, declines in the hippocampus of aged rats and its overexpression results in enhancement of spatial memory along with reduction of the sAHP [193,194]. Likewise, in skeletal and cardiac muscle, the cause for RyR dysregulation in aging neurons is oxidation by ROS. Dithiothreitol (DTT), a reducing agent, decreases the sAHP in old but not young rats, and blockade of RyRs or depletion of intracellular calcium stores suppresses DTT effects, whereas DTT-mediated decrease in sAHP is not affected by inhibition of other Ca2+ pathways including VDCC-mediated pathways [93,192,195]. Using single RyRs from rat brain cortex incorporated into lipid bilayers, Bull et al. showed that the activation of the RyR by calcium depends on the redox state of the receptor [196,197]. They further showed that the RyR2 and RyR3 from the cortex of rat brains subjected to cerebral ischemia opened more readily and thus leaked more calcium than normal, due to S-glutathionylation of unidentified cysteine residues [198].
The Genetic Basis of Malignant Hyperthermia
Published in S. Tsuyoshi Ohnishi, Tomoko Ohnishi, Malignant Hyperthermia, 1994
David H. MacLennan, Michael S. Phillips, Yilin Zhang
We have shown that two genes encode Ca2+ release channels of the SR by cloning full length cDNAs encoding the rabbit,16 human,16 and porcine30 skeletal muscle isoforms (RYR1) and the rabbit13 cardiac and brain isoform (RYR2). More recently, a third RYR gene (RYR3) has been cloned.31,32RYR1 encodes the Ca2+ release channel of both slow- and fast-twitch skeletal muscle; RYR2 encodes a second Ca2+ release channel that is expressed in cardiac muscle and brain; and RYR3 appears to be expressed most abundantly in brain and specific smooth muscles,32 although it is also expressed in lung.31 We have localized RYR1 on human chromosome 19ql3. 1 (Figure 2)33 and RYR2 on human chromosome 1.18 We also identified a series of restriction-fragment length polymorphisms (RFLPs) in RYR1 that permitted us to study linkage between inheritance of one or more of these RFLPs and inheritance of MH, defined by CHC tests.34 Cosegregation was found in 23 meioses in 9 families, with no recombinants, leading to a probability of about 16,000 to 1 that the two loci are linked. 34
Malignant syndromes: current advances
Published in Expert Opinion on Drug Safety, 2021
Minghua Tao, Jiyuan Li, Xuefeng Wang, Xin Tian
MH is a drug-related genetic disease caused by functional defects in the ryanodine receptor (RYR). RYRs are a family of intracellular Ca2+ release channels that play a pivotal role in regulating intracellular Ca2+ homeostasis in muscle cells and neurons [33,34]. The RYR genes encode 3 isoforms with different properties and tissue distributions: RYR1 (skeletal muscle), RYR2 (cardiac muscle), and RYR3 (brain and some smooth muscle) [35]. Variants in the 3 RYR isoforms lead to different diseases, depending on their organ location and the dysfunctions involved (see Figure 1).
Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases
Published in Expert Opinion on Therapeutic Targets, 2022
Mohit M. Hulsurkar, Satadru K. Lahiri, Jason Karch, Meng C. Wang, Xander H.T. Wehrens
Beyond its known function in SR Ca2+ handling, multiple studies have suggested an additional role of RyR2 in overall cellular Ca2+ homeostasis by regulating mitochondrial and lysosomal Ca2+ transport [46,47]. A recent study showed a strong correlation between increased SR Ca2+ leak due to RyR2 hyperglycation and mitochondrial damage in aged hearts [46] suggesting a role of RyR2 in mitochondrial bioenergetics. Another study revealed an interesting feedback loop where RyR2-mediated SR Ca2+ leak increases mitochondrial ROS, which further oxidizes RyR2 in AF [48]. This RyR2-redox feedback loop was validated in a myocardial infarction model where impeding RyR2-mediated Ca2+ leak reduced mitochondrial Ca2+ overload and damage [49]. Further mechanistic studies may reveal if RyR2 directly affects mitochondrial Ca2+ signaling and function by either residing in the mitochondrial membrane or by interacting with mitochondrial proteins across SR-mitochondria contact sites. Indeed, a recent proteomics study revealed that several of the most abundant RyR2-binding proteins are mitochondrial proteins, including Aifm1, Cpt1b, and Idh3b [50]. The role of RyR2 in lysosomes has not been studied in detail although the identification of SR-lysosomes microdomains [47] suggests that RyR2 is involved in lysosomal Ca2+ regulation as well. One study in arterial smooth muscle cells revealed that lysosomal nicotinic acid adenine dinucleotide phosphate (NAADP) binds RyR3 to mediate Ca2+ regulation [51]. Taken together, mechanistic studies dissecting RyR2 gene regulation, epigenetic modifications, post-translation regulations, sub-cellular localization, and organelle-specific Ca2+ handling could establish RyR2 inhibitory therapies as a primary treatment for various heart diseases.