Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders

Treves, Susan; Anderson, Ayuk A.; Ducreux, Sylvie; Divet, Alexandra; Bleunven, Christophe; Grasso, Cristiano; Paesante, Silvia; Zorzato, Francesco

doi:10.1016/j.nmd.2005.06.008

Cited by 130 publications

(99 citation statements)

References 127 publications

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“…Because MH syndromes are linked to mutations in the RyR1 channel in various vertebrates, as well as in humans (2,4,34,35), and because dantrolene binds to a specific site on RyR1 (36), previous studies have focused on the role of dantrolene in modulating RyR1 channel activity. Functional studies demonstrate only partial inhibition of Ca 2ϩ release from isolated SR membrane vesicles (11,12,15) and partial suppression of the elemental Ca 2ϩ spark signals in adult muscle fibers (16).…”

Section: Discussionmentioning

confidence: 99%

“…2 is a potentially fatal pharmacogenetic syndrome in which exposure to volatile anesthetics triggers uncontrolled elevation of myoplasmic Ca 2ϩ concentrations ([Ca 2ϩ ] i ), skeletal muscle hypercontracture, and hypermetabolism, resulting in a dramatic rise in body temperature (1,2). Mutations in the type 1 ryanodine receptor (RyR1), the major Ca 2ϩ release channel in skeletal muscle, are linked to MH susceptibility in pigs in an autosomal recessive manner (3)(4)(5).…”

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 99%

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Azumolene Inhibits a Component of Store-operated Calcium Entry Coupled to the Skeletal Muscle Ryanodine Receptor

Zhao

Weisleder

Han

et al. 2006

Journal of Biological Chemistry

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Dantrolene reduces the elevated myoplasmic Ca2؉ generated during malignant hyperthermia, a pharmacogenetic crisis triggered by volatile anesthetics. Although specific binding of dantrolene to the type 1 ryanodine receptor (RyR1), the Ca 2؉ release channel of skeletal muscle sarcoplasmic reticulum, has been demonstrated, there is little evidence for direct dantrolene inhibition of RyR1 channel function. Recent studies suggest storeoperated Ca 2؉ entry (SOCE) contributes to skeletal muscle function, but the effect of dantrolene on this pathway has not been examined. Here we show that azumolene, an equipotent dantrolene analog, inhibits a component of SOCE coupled to activation of RyR1 by caffeine and ryanodine, whereas the SOCE component induced by thapsigargin is not affected. Our data suggest that azumolene distinguishes between two mechanisms of cellular signaling to SOCE in skeletal muscle, one that is coupled to and one independent from RyR1. Malignant hyperthermia (MH)2 is a potentially fatal pharmacogenetic syndrome in which exposure to volatile anesthetics triggers uncontrolled elevation of myoplasmic Ca 2ϩ concentrations ([Ca 2ϩ ] i ), skeletal muscle hypercontracture, and hypermetabolism, resulting in a dramatic rise in body temperature (1, 2). Mutations in the type 1 ryanodine receptor (RyR1), the major Ca 2ϩ release channel in skeletal muscle, are linked to MH susceptibility in pigs in an autosomal recessive manner (3-5). In humans, MH is transmitted as an autosomal dominant trait with incomplete penetrance, and the more than 80 mutations in RyR1 that have been identified appear in only about 50% of affected families (6, 7). Muscle bundles from MH-susceptible patients are hypersensitive to RyR1 agonists, including caffeine, Ca 2ϩ , and halothane (8, 9), the latter a member of the class of volatile anesthetics that triggers MH. Thus, the loss of control of RyR1-mediated Ca 2ϩ release likely contributes to the elevation of [Ca 2ϩ ] i observed in MH patients. To date, the only effective treatment for MH is dantrolene sodium, a skeletal muscle relaxant, which suppresses the uncontrolled rise in myoplasmic Ca 2ϩ , presumably by targeting RyR1 and suppressing its Ca 2ϩ channel activity (10 -12). Azumolene sodium is a structurally similar, equipotent analog of dantrolene, with an ϳ30-fold greater water solubility (13,14).Whereas hyperactivity or leakiness of the RyR1 channel has been described as the primary physiological defect in MH-susceptible muscle, the molecular mechanism underlying the suppression of [ -sensitive fluorescence measurements of RyR1-dependent intracellular Ca 2ϩ transients and extracellular Ca 2ϩ entry via SOCE, we show that azumolene inhibits SOCE both in skeletal muscle fibers and in cultured cells expressing RyR1. Our results reveal two modes of SOCE activation. One mode is RyR1-dependent and can be inhibited by the action of azumolene; the other is RyR1-independent and is insensitive to azumolene. EXPERIMENTAL PROCEDURESCell Culture-C1148 cells, a Chinese hamster ovary (CHO) ce...

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Section: Discussionmentioning

confidence: 99%

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 99%

Azumolene Inhibits a Component of Store-operated Calcium Entry Coupled to the Skeletal Muscle Ryanodine Receptor

Zhao

Weisleder

Han

et al. 2006

Journal of Biological Chemistry

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“…The simplest interpretation of our structural findings that is consistent with domaindomain interaction hypothesis of Ikemoto (12) is that the NH 2 -terminal mutations are located in domain 5 and the central mutations are in domain 6, and that alteration of interactions between these two domains is responsible for the observed phenotypes. However, we cannot yet exclude the other domains in the clamp-shaped structure (7,8,10 in Fig. 7) until the boundaries of the mutation hot spots are better defined.…”

Section: The Clamp-shaped Structure Of Ryr Is a Crucial Part Of The Cmentioning

confidence: 99%

“…A common finding of these studies is that most of the RyR2 mutations enhance the activity of the channel upon stimulation (1)(2)(3)(4). This enhancement of function activity is also a consistent feature with most of the RyR1 MH and CCD mutations (5)(6)(7). However, the precise mechanism by which channel function is altered by disease-linked mutations is not well defined.…”

mentioning

confidence: 94%

Localization of an NH2-terminal Disease-causing Mutation Hot Spot to the “Clamp” Region in the Three-dimensional Structure of the Cardiac Ryanodine Receptor

Wang

Chen

Cai

et al. 2007

Journal of Biological Chemistry

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A region between residues 414 and 466 in the cardiac ryanodine receptor (RyR2) harbors more than half of the known NH 2 -terminal mutations associated with cardiac arrhythmias and sudden death. To gain insight into the structural basis of this NH 2 -terminal mutation hot spot, we have determined its location in the three-dimensional structure of RyR2. Green fluorescent protein (GFP), used as a structural marker, was inserted into the middle of this mutation hot spot after Ser-437 in the RyR2 sequence. 2؉ release similar to that in cells expressing RyR2-wt. The three-dimensional structure of the purified RyR2 S437-GFP was reconstructed using cryo-electron microscopy and single particle image processing. Subtraction of the three-dimensional reconstructions of RyR2-wt and RyR2 S437-GFP revealed the location of the inserted GFP, and hence the NH 2 -terminal mutation hot spot, in a region between domains 5 and 9 in the clamp-shaped structure. This location is close to a previously mapped central disease-causing mutation site located in a region between domains 5 and 6. These results, together with findings from previous studies, suggest that the proposed interactions between the NH 2 -terminal and central regions of RyR2 are likely to take place between domains 5 and 6 and that the clamp-shaped structure, which shows substantial conformational differences between the closed and open states, is highly susceptible to disease-causing mutations.Cardiac arrhythmia, a leading cause of sudden death, has been linked to a number of genes encoding ion channels, including the cardiac sarcoplasmic recticulum Ca 2ϩ release channel (ryanodine receptor (RyR) type 2) 3 (1-4). To date, more than 40 mutations in RyR2 have been associated with at least two forms of cardiac arrhythmias, catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Most of these mutations are located in the NH 2 -terminal region (between amino acids 164 and 466), central region (between amino acids 2246 and 2504), and the COOH-terminal region (between amino acids 3778 and 4959) of RyR2 (Fig. 1). Interestingly, those mutations in the skeletal muscle RyR (RyR1) that are linked to malignant hyperthermia (MH) and central core disease (CCD) are largely clustered in the corresponding regions of RyR1; some sites even correspond exactly (2, 4) (Fig. 1). These similar distributions suggest that the molecular mechanisms by which these disease-linked RyR1 and RyR2 mutations alter the intrinsic properties of the channel are conserved.A number of disease-linked RyR2 mutations have been expressed and functionally characterized. A common finding of these studies is that most of the RyR2 mutations enhance the activity of the channel upon stimulation (1-4). This enhancement of function activity is also a consistent feature with most of the RyR1 MH and CCD mutations (5-7). However, the precise mechanism by which channel function is altered by disease-linked mutations is not well defined. Wehrens et al. (8) ...

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“…The calculated frequency of RYR1 mutations is approximately 1:3000 making it one of the most commonly mutated genes associated with neuromuscular disorders [38][39][40]. A number of reviews concerning the frequency, disease associations and functional impact of RYR1 mutations have been published in recent years and the reader is referred to these for a more in depth description (for example see [12][13][14][15][16][17][18][19][20][21][22][23][24][41][42][43][44][45]). The disease phenotype resulting from RYR1 mutations largely depends on their location within the RYR1 coding sequence and whether the mutations are dominant or recessive.…”

Section: Disorders Associated With Ryr1 Mutationsmentioning

confidence: 99%

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

Treves

Jungbluth

Voermans

et al. 2017

Seminars in Cell & Developmental Biology

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a b s t r a c tThe physiological process by which Ca 2+ is released from the sarcoplasmic reticulum is called excitationcontraction coupling; it is initiated by an action potential which travels deep into the muscle fiber where it is sensed by the dihydropyridine receptor, a voltage sensing L-type Ca 2+ channel localized on the transverse tubules. Voltage-induced conformational changes in the dihydropyridine receptor activate the ryanodine receptor Ca 2+ release channel of the sarcoplasmic reticulum. The released Ca 2+ binds to troponin C, enabling contractile thick-thin filament interactions. The Ca 2+ is subsequently transported back into the sarcoplasmic reticulum by specialized Ca 2+ pumps (SERCA), preparing the muscle for a new cycle of contraction. Although other proteins are involved in excitation-contraction coupling, the mechanism described above emphasizes the unique role played by the two Ca 2+ channels (the dihydropyridine receptor and the ryanodine receptor), the SERCA Ca 2+ pumps and the exquisite spatial organization of the membrane compartments endowed with the proteins responsible for this mechanism to function rapidly and efficiently. Research over the past two decades has uncovered the fine details of excitation-contraction coupling under normal conditions while advances in genomics have helped to identify mutations in novel genes in patients with neuromuscular disorders. While it is now clear that many patients with congenital muscle diseases carry mutations in genes encoding proteins directly involved in Ca 2+ homeostasis, it has become apparent that mutations are also present in genes encoding for proteins not thought to be directly involved in Ca 2+ regulation. Ongoing research in the field now focuses on understanding the functional effect of individual mutations, as well as understanding the role of proteins not specifically located in the sarcoplasmic reticulum which nevertheless are involved in Ca 2+ regulation or excitation-contraction coupling. The principal challenge for the future is the identification of drug targets that can be pharmacologically manipulated by small molecules, with the ultimate aim to improve muscle function and quality of life of patients with congenital muscle disorders. The aim of this review is to give an overview of the most recent findings concerning Ca 2+ dysregulation and its impact on muscle function in patients with congenital muscle disorders due to mutations in proteins involved in excitation-contraction coupling and more broadly on Ca 2+ homeostasis.

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Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders

Cited by 130 publications

References 127 publications

Azumolene Inhibits a Component of Store-operated Calcium Entry Coupled to the Skeletal Muscle Ryanodine Receptor

Azumolene Inhibits a Component of Store-operated Calcium Entry Coupled to the Skeletal Muscle Ryanodine Receptor

Localization of an NH2-terminal Disease-causing Mutation Hot Spot to the “Clamp” Region in the Three-dimensional Structure of the Cardiac Ryanodine Receptor

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

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