Novel regulators of RyR Ca2+ release channels: Insight into molecular changes in genetically-linked myopathies

Angela F. Dulhunty, N A Beard, P Pouliquin, Takashi Kimura

    Research output: Contribution to journalReview article

    19 Citations (Scopus)

    Abstract

    There are many mutations in the ryanodine receptor (RyR) Ca2+ release channel that are implicated in skeletal muscle disorders and cardiac arrhythmias. More than 80 mutations in the skeletal RyR1 have been identified and linked to malignant hyperthermia, central core disease or multi-minicore disease, while more than 40 mutations in the cardiac RyR2 lead to ventricular arrhythmias and sudden cardiac death in patients with structurally normal hearts. These RyR mutations cause diverse changes in RyR activity which either excessively activate or block the channel in a manner that disrupts Ca2+ signalling in the muscle fibres. In a different myopathy, myotonic dystrophy (DM), a juvenile isoform of the skeletal RyR is preferentially expressed in adults. There are two regions of RyR1 that are variably spiced and developmentally regulated (ASI and ASII). The juvenile isoform (ASI(-)) is less active than the adult isoform (ASI(+)) and its over-expression in adults with DM may contribute to functional changes. Finally, mutations in an important regulator of the RyR, the Ca2+ binding protein calsequestrin (CSQ), have been linked to a disruption of Ca2+ homeostasis in cardiac myocytes that results in arrhythmias. We discuss evidence supporting the hypothesis that mutations in each of these situations alter protein/protein interactions within the RyR complex or between the RyR and its associated proteins. The disruption of these protein-protein interactions can lead either to excess Ca2+ release or reduced Ca2+ release and thus to abnormal Ca2+ homeostasis. Much of the evidence for disruption of protein-protein interactions has been provided by the actions of a group of novel RyR regulators, domain peptides with sequences that correspond to sequences within the RyR and which compete with the endogenous residues for their interaction sites.

    Original languageEnglish
    Pages (from-to)351-365
    Number of pages15
    JournalJournal of Muscle Research and Cell Motility
    Volume27
    Issue number5-7
    DOIs
    Publication statusPublished - 2006

    Fingerprint

    Ryanodine Receptor Calcium Release Channel
    Muscular Diseases
    Mutation
    Proteins
    Cardiac Arrhythmias
    Protein Isoforms
    Muscle
    Central Core Myopathy
    Homeostasis
    Calsequestrin
    Malignant Hyperthermia
    Myotonic Dystrophy
    Sudden Cardiac Death
    Cardiac Myocytes
    Carrier Proteins
    Skeletal Muscle

    Cite this

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    title = "Novel regulators of RyR Ca2+ release channels: Insight into molecular changes in genetically-linked myopathies",
    abstract = "There are many mutations in the ryanodine receptor (RyR) Ca2+ release channel that are implicated in skeletal muscle disorders and cardiac arrhythmias. More than 80 mutations in the skeletal RyR1 have been identified and linked to malignant hyperthermia, central core disease or multi-minicore disease, while more than 40 mutations in the cardiac RyR2 lead to ventricular arrhythmias and sudden cardiac death in patients with structurally normal hearts. These RyR mutations cause diverse changes in RyR activity which either excessively activate or block the channel in a manner that disrupts Ca2+ signalling in the muscle fibres. In a different myopathy, myotonic dystrophy (DM), a juvenile isoform of the skeletal RyR is preferentially expressed in adults. There are two regions of RyR1 that are variably spiced and developmentally regulated (ASI and ASII). The juvenile isoform (ASI(-)) is less active than the adult isoform (ASI(+)) and its over-expression in adults with DM may contribute to functional changes. Finally, mutations in an important regulator of the RyR, the Ca2+ binding protein calsequestrin (CSQ), have been linked to a disruption of Ca2+ homeostasis in cardiac myocytes that results in arrhythmias. We discuss evidence supporting the hypothesis that mutations in each of these situations alter protein/protein interactions within the RyR complex or between the RyR and its associated proteins. The disruption of these protein-protein interactions can lead either to excess Ca2+ release or reduced Ca2+ release and thus to abnormal Ca2+ homeostasis. Much of the evidence for disruption of protein-protein interactions has been provided by the actions of a group of novel RyR regulators, domain peptides with sequences that correspond to sequences within the RyR and which compete with the endogenous residues for their interaction sites.",
    keywords = "Amino Acid Sequence, Animals, Arrhythmias, Cardiac, Calcium, Calsequestrin, Homeostasis, Humans, Molecular Sequence Data, Muscle Cells, Muscular Diseases, Mutation, Peptides, Protein Binding, Protein Structure, Tertiary, Ryanodine Receptor Calcium Release Channel",
    author = "Dulhunty, {Angela F.} and Beard, {N A} and P Pouliquin and Takashi Kimura",
    year = "2006",
    doi = "10.1007/s10974-006-9086-1",
    language = "English",
    volume = "27",
    pages = "351--365",
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    Novel regulators of RyR Ca2+ release channels: Insight into molecular changes in genetically-linked myopathies. / Dulhunty, Angela F.; Beard, N A; Pouliquin, P; Kimura, Takashi.

    In: Journal of Muscle Research and Cell Motility, Vol. 27, No. 5-7, 2006, p. 351-365.

    Research output: Contribution to journalReview article

    TY - JOUR

    T1 - Novel regulators of RyR Ca2+ release channels: Insight into molecular changes in genetically-linked myopathies

    AU - Dulhunty, Angela F.

    AU - Beard, N A

    AU - Pouliquin, P

    AU - Kimura, Takashi

    PY - 2006

    Y1 - 2006

    N2 - There are many mutations in the ryanodine receptor (RyR) Ca2+ release channel that are implicated in skeletal muscle disorders and cardiac arrhythmias. More than 80 mutations in the skeletal RyR1 have been identified and linked to malignant hyperthermia, central core disease or multi-minicore disease, while more than 40 mutations in the cardiac RyR2 lead to ventricular arrhythmias and sudden cardiac death in patients with structurally normal hearts. These RyR mutations cause diverse changes in RyR activity which either excessively activate or block the channel in a manner that disrupts Ca2+ signalling in the muscle fibres. In a different myopathy, myotonic dystrophy (DM), a juvenile isoform of the skeletal RyR is preferentially expressed in adults. There are two regions of RyR1 that are variably spiced and developmentally regulated (ASI and ASII). The juvenile isoform (ASI(-)) is less active than the adult isoform (ASI(+)) and its over-expression in adults with DM may contribute to functional changes. Finally, mutations in an important regulator of the RyR, the Ca2+ binding protein calsequestrin (CSQ), have been linked to a disruption of Ca2+ homeostasis in cardiac myocytes that results in arrhythmias. We discuss evidence supporting the hypothesis that mutations in each of these situations alter protein/protein interactions within the RyR complex or between the RyR and its associated proteins. The disruption of these protein-protein interactions can lead either to excess Ca2+ release or reduced Ca2+ release and thus to abnormal Ca2+ homeostasis. Much of the evidence for disruption of protein-protein interactions has been provided by the actions of a group of novel RyR regulators, domain peptides with sequences that correspond to sequences within the RyR and which compete with the endogenous residues for their interaction sites.

    AB - There are many mutations in the ryanodine receptor (RyR) Ca2+ release channel that are implicated in skeletal muscle disorders and cardiac arrhythmias. More than 80 mutations in the skeletal RyR1 have been identified and linked to malignant hyperthermia, central core disease or multi-minicore disease, while more than 40 mutations in the cardiac RyR2 lead to ventricular arrhythmias and sudden cardiac death in patients with structurally normal hearts. These RyR mutations cause diverse changes in RyR activity which either excessively activate or block the channel in a manner that disrupts Ca2+ signalling in the muscle fibres. In a different myopathy, myotonic dystrophy (DM), a juvenile isoform of the skeletal RyR is preferentially expressed in adults. There are two regions of RyR1 that are variably spiced and developmentally regulated (ASI and ASII). The juvenile isoform (ASI(-)) is less active than the adult isoform (ASI(+)) and its over-expression in adults with DM may contribute to functional changes. Finally, mutations in an important regulator of the RyR, the Ca2+ binding protein calsequestrin (CSQ), have been linked to a disruption of Ca2+ homeostasis in cardiac myocytes that results in arrhythmias. We discuss evidence supporting the hypothesis that mutations in each of these situations alter protein/protein interactions within the RyR complex or between the RyR and its associated proteins. The disruption of these protein-protein interactions can lead either to excess Ca2+ release or reduced Ca2+ release and thus to abnormal Ca2+ homeostasis. Much of the evidence for disruption of protein-protein interactions has been provided by the actions of a group of novel RyR regulators, domain peptides with sequences that correspond to sequences within the RyR and which compete with the endogenous residues for their interaction sites.

    KW - Amino Acid Sequence

    KW - Animals

    KW - Arrhythmias, Cardiac

    KW - Calcium

    KW - Calsequestrin

    KW - Homeostasis

    KW - Humans

    KW - Molecular Sequence Data

    KW - Muscle Cells

    KW - Muscular Diseases

    KW - Mutation

    KW - Peptides

    KW - Protein Binding

    KW - Protein Structure, Tertiary

    KW - Ryanodine Receptor Calcium Release Channel

    U2 - 10.1007/s10974-006-9086-1

    DO - 10.1007/s10974-006-9086-1

    M3 - Review article

    VL - 27

    SP - 351

    EP - 365

    JO - Journal of Muscle Research and Cell Motility

    JF - Journal of Muscle Research and Cell Motility

    SN - 0142-4319

    IS - 5-7

    ER -