Myoplasmic resting Ca2+ regulation by ryanodine receptors is under the control of a novel Ca2+-binding region of the receptor

Chen, Yanyi; Xue, Shenghui; Zou, Juan; López, José R.; Yang, Jenny J.; Pérez, Claudio F.

doi:10.1042/bj20131553

Cited by 14 publications

(11 citation statements)

References 47 publications

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“…The SR Ca 2+ ATP-ase has been shown to be one of the pathways by which Ca 2+ leaks out of the SR [ 29 , 31 – 33 ]. The ryanodine-receptor Ca 2+ -release channel (RyR1) is another possible leak pathway [ 34 , 35 ], but since the expression of RyR1 was not increased in Actn3 KO muscle ( Fig. 5 A ), this pathway would not contribute to the increased leak rate of KO fibres, unless the RyR1 channels had become more “leaky”.…”

Section: Discussionmentioning

confidence: 99%

Altered Ca2+ Kinetics Associated with α-Actinin-3 Deficiency May Explain Positive Selection for ACTN3 Null Allele in Human Evolution

et al. 2015

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Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common null polymorphism (R577X) in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities. In the human genome, it is very difficult to find single-gene loss-of-function variants that bear signatures of positive selection, yet intriguingly, the ACTN3 null variant has undergone strong positive selection during recent evolution, appearing to provide a survival advantage where food resources are scarce and climate is cold. We have previously demonstrated that α-actinin-3 deficiency in the Actn3 KO mouse results in a shift in fast-twitch fibres towards oxidative metabolism, which would be more “energy efficient” in famine, and beneficial to endurance performance. Prolonged exposure to cold can also induce changes in skeletal muscle similar to those observed with endurance training, and changes in Ca2+ handling by the sarcoplasmic reticulum (SR) are a key factor underlying these adaptations. On this basis, we explored the effects of α-actinin-3 deficiency on Ca2+ kinetics in single flexor digitorum brevis muscle fibres from Actn3 KO mice, using the Ca2+-sensitive dye fura-2. Compared to wild-type, fibres of Actn3 KO mice showed: (i) an increased rate of decay of the twitch transient; (ii) a fourfold increase in the rate of SR Ca2+ leak; (iii) a threefold increase in the rate of SR Ca2+ pumping; and (iv) enhanced maintenance of tetanic Ca2+ during fatigue. The SR Ca2+ pump, SERCA1, and the Ca2+-binding proteins, calsequestrin and sarcalumenin, showed markedly increased expression in muscles of KO mice. Together, these changes in Ca2+ handling in the absence of α-actinin-3 are consistent with cold acclimatisation and thermogenesis, and offer an additional explanation for the positive selection of the ACTN3 577X null allele in populations living in cold environments during recent evolution.

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Section: Discussionmentioning

confidence: 99%

Altered Ca2+ Kinetics Associated with α-Actinin-3 Deficiency May Explain Positive Selection for ACTN3 Null Allele in Human Evolution

et al. 2015

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“…The disruption of the NTDA + /CD interaction is accompanied by an upward movement of the CTD in mutant RyR1, which, in turn, alters the Ca 2+ binding site. In both isoforms, the Ca 2+ binding site ( 23 , 27 , 30 , 31 ) consists of key negative residues in the CTD and CD that reorient to coordinate the Ca 2+ ion causing channel opening. In RyR1 R164C, the upward movement of the CTD brings the backbone carbonyl of T5001 closer to the side-chain carbonyls of E3893 and E3967 of the CD [ Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural mechanism of two gain-of-function cardiac and skeletal RyR mutations at an equivalent site by cryo-EM

Iyer

Nayak

et al. 2020

Sci. Adv.

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Mutations in ryanodine receptors (RyRs), intracellular Ca2+ channels, are associated with deadly disorders. Despite abundant functional studies, the molecular mechanism of RyR malfunction remains elusive. We studied two single-point mutations at an equivalent site in the skeletal (RyR1 R164C) and cardiac (RyR2 R176Q) isoforms using ryanodine binding, Ca2+ imaging, and cryo–electron microscopy (cryo-EM) of the full-length protein. Loss of the positive charge had greater effect on the skeletal isoform, mediated via distortion of a salt bridge network, a molecular latch inducing rotation of a cytoplasmic domain, and partial progression to open-state traits of the large cytoplasmic assembly accompanied by alteration of the Ca2+ binding site, which concur with the major “hyperactive” feature of the mutated channel. Our cryo-EM studies demonstrated the allosteric effect of a mutation situated ~85 Å away from the pore and identified an isoform-specific structural effect.

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“…Nevertheless, a limit of our study is the use of nonmuscle cells for the in vitro characterization of mutants. The c.9293G>T (p.S3098I) substitution was predicted to have a pathological character and affects a residue located in a region involved in the homeostasis of intracellular calcium (amino acids 3770-4007) [64]. On the basis of our experiments, we could not discriminate between the effects of the two variants.…”

Section: Discussionmentioning

confidence: 84%

RYR1Sequence Variants in Myopathies: Expression and Functional Studies in Two Families

Zullo

Perrotta

D'Angelo

et al. 2019

BioMed Research International

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The skeletal muscle ryanodine receptor (RyR1), i.e., the Ca2+ channel of the sarco/endoplasmic reticulum (S/ER), and the voltage-dependent calcium channel Cav1.1 are the principal channels involved in excitation-contraction coupling in skeletal muscle. RYR1 gene variants are linked to distinct skeletal muscle disorders, including malignant hyperthermia susceptibility and central core disease (CCD), mainly with autosomal dominant inheritance, and autosomal recessive myopathies with a broad phenotypic and histopathological spectrum. The age at onset of RYR1-related myopathies varies from infancy to adulthood. We report the identification of four RYR1 variants in two Italian families: one with myopathy and variants c.4003C>T (p.R1335C) and c.7035C>A (p.S2345R), and another with CCD and variants c.9293G>T (p.S3098I) and c.14771_14772insTAGACAGGGTGTTGCTCTGTTGCCCTTCTT (p.F4924_V4925insRQGVALLPFF). We demonstrate that, in patient-specific lymphoblastoid cells, the c.4003C>T (p.R1335C) variant is not expressed and the in-frame 30-nucleotide insertion variant is expressed at a low level. Moreover, Ca2+ release in response to the RyR1 agonist 4-chloro-m-cresol and to thapsigargin showed that the c.7035C>A (p.S2345R) variant causes depletion of S/ER Ca2+ stores and that the compound heterozygosity for variant c.9293G>T (p.S3098I) and the 30-nucleotide insertion increases RyR1-dependent Ca2+ release without affecting ER Ca2+ stores. In conclusion, we detected and functionally characterized disease-causing variants of the RyR1 channel in patient-specific lymphoblastoid cells.

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Myoplasmic resting Ca2+ regulation by ryanodine receptors is under the control of a novel Ca2+-binding region of the receptor

Cited by 14 publications

References 47 publications

Altered Ca2+ Kinetics Associated with α-Actinin-3 Deficiency May Explain Positive Selection for ACTN3 Null Allele in Human Evolution

Altered Ca2+ Kinetics Associated with α-Actinin-3 Deficiency May Explain Positive Selection for ACTN3 Null Allele in Human Evolution

Structural mechanism of two gain-of-function cardiac and skeletal RyR mutations at an equivalent site by cryo-EM

RYR1Sequence Variants in Myopathies: Expression and Functional Studies in Two Families

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