Ryanodine Receptor Type 1 (RyR1) Mutations C4958S and C4961S Reveal Excitation-coupled Calcium Entry (ECCE) Is Independent of Sarcoplasmic Reticulum Store Depletion

Hurne, Alanna M.; OʼBrien, Jennifer; Wingrove, Douglas E.; Cherednichenko, Gennady; Allen, Paul D.; Beam, Kurt G.; Pessah, Isaac N.

doi:10.1074/jbc.m506441200

Cited by 55 publications

(75 citation statements)

References 69 publications

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“…ECCE is not sensitive to Ca 2ϩ store depletion but is activated by membrane depolarization and is sensitive to RyR1 conformation and mutations (39,40). Furthermore, they have presented preliminary evidence that dantrolene also affects ECCE, but not TG-induced SOCE, thereby discriminating between the two processes (41).…”

Section: Discussionmentioning

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%

“…Recent studies from Pessah and co-workers (39,40) have demonstrated a process of excitation-coupled Ca 2ϩ entry (ECCE) experimentally distinct from SOCE in cultured myotubes. ECCE is not sensitive to Ca 2ϩ store depletion but is activated by membrane depolarization and is sensitive to RyR1 conformation and mutations (39,40).…”

Section: Discussionmentioning

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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“…Depolarization-dependent Ca 2+ entry is influenced by expression of various constituents of the EC coupling apparatus including the α 1S and β 1a subunits of Ca V 1.1, 4,5,10 RyR1, 4,5,9-11 JP-45, 19 and calsequestrin1. 19 In the present work, we present the first example of modulation of this mysterious mode of Ca 2+ influx into skeletal muscle by dynamically-regulated cell signaling molecules (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Of these functions, the fundamental abilities of Ca V 1.1 to engage EC coupling by gating the type 1 ryanodine receptor (RyR1) and to conduct L-type current are well-documented. 6 However, the specific route of Ca 2+ permeation for depolarizationdependent entry remains a matter of debate.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 Depolarization-dependent Ca 2+ entry, also referred to as Excitation-Coupled Ca 2+ Entry (ECCE), was first identified in dysgenic (Ca V 1.1 null) myotubes expressing a pore mutant with a minimal ability to conduct Ca 2+ . 4 Since this type of Ca 2+ entry was absent in naïve dysgenic and dyspedic (RyR1 null) myotubes, 4,5,9 the existence of a distinct Ca 2+ channel whose gating was coupled to depolarization-dependent rearrangements in the EC coupling apparatus was proposed. Later on, the abundance of genetic (i.e., absence in dysgenic, dyspedic and Ca V β 1 null myotubes) and pharmacological (i.e., sensitivity to Gd 3+ , La 3+ , 2-aminoethyl diphenylborate, SKF 96356, nifedipine and dantrolene) characteristics shared by depolarization-dependent Ca 2+ entry and the conventional L-type means of Ca 2+ entry led to the idea that these pathways were, for the most part, one and the same.…”

Section: Introductionmentioning

confidence: 99%

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RGK protein-mediated impairment of slow depolarization- dependent Ca²⁺entry into developing myotubes

et al. 2014

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Calcium in Health and Disease

Brini

Ottolini

Calì

et al. 2013

Metal Ions in Life Sciences

116

107

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Evolution has exploited the chemical properties of Ca(2+), which facilitate its reversible binding to the sites of irregular geometry offered by biological macromolecules, to select it as a carrier of cellular signals. A number of proteins bind Ca(2+) to specific sites: those intrinsic to membranes play the most important role in the spatial and temporal regulation of the concentration and movements of Ca(2+) inside cells. Those which are soluble, or organized in non-membranous structures, also decode the Ca(2+) message to be then transmitted to the targets of its regulation. Since Ca(2+) controls the most important processes in the life of cells, it must be very carefully controlled within the cytoplasm, where most of the targets of its signaling function reside. Membrane channels (in the plasma membrane and in the organelles) mediate the entrance of Ca(2+) into the cytoplasm, ATPases, exchangers, and the mitochondrial Ca(2+) uptake system remove Ca(2+) from it. The concentration of Ca(2+) in the external spaces, which is controlled essentially by its dynamic exchanges in the bone system, is much higher than inside cells, and can, under conditions of pathology, generate a situation of dangerous internal Ca(2+) overload. When massive and persistent, the Ca(2+) overload culminates in the death of the cell. Subtle conditions of cellular Ca(2+) dyshomeostasis that affect individual systems that control Ca(2+), generate cell disease phenotypes that are particularly severe in tissues in which the signaling function of Ca(2+) has special importance, e.g., the nervous system.

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Ryanodine Receptor Type 1 (RyR1) Mutations C4958S and C4961S Reveal Excitation-coupled Calcium Entry (ECCE) Is Independent of Sarcoplasmic Reticulum Store Depletion

Cited by 55 publications

References 69 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

RGK protein-mediated impairment of slow depolarization- dependent Ca²⁺entry into developing myotubes

Calcium in Health and Disease

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Ryanodine Receptor Type 1 (RyR1) Mutations C4958S and C4961S Reveal Excitation-coupled Calcium Entry (ECCE) Is Independent of Sarcoplasmic Reticulum Store Depletion

Cited by 55 publications

References 69 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

RGK protein-mediated impairment of slow depolarization- dependent Ca2+entry into developing myotubes

Calcium in Health and Disease

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Product

Resources

About

RGK protein-mediated impairment of slow depolarization- dependent Ca²⁺entry into developing myotubes