Regulation of mammalian ryanodine receptors

Meissner, Gerhard

doi:10.2741/a899

Cited by 163 publications

(148 citation statements)

References 64 publications

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…Moreover, inactivation of ryanodine receptors starts only at around 50-100 mM [Ca 2 þ ]. 32 Thus, the Ca 2 þ increase caused by the reduction of mitochondrial Ca 2 þ uptake in the vicinity of ryanodine receptor may well be insufficient to inhibit channel activity.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1α

et al. 2005

View full text Add to dashboard Cite

Mitochondrial Ca 2 þ uptake controls cellular functions as diverse as aerobic metabolism, cytosolic Ca 2 þ signalling and mitochondrial participation in apoptosis. Modulatory inputs converging on the organelle can regulate this process, determining the final outcome of Ca 2 þ -mediated cell stimulation. We investigated in HeLa cells and primary skeletal myotubes the effect on Ca 2 þ signalling of the transcriptional peroxisome-proliferator-activated-receptor-c-coactivator-1a (PGC-1a), which triggers organelle biogenesis and modifies the mitochondrial proteome. PGC-1a selectively reduced mitochondrial Ca 2 þ responses to cell stimulation by reducing the efficacy of mitochondrial Ca 2 þ uptake sites and increasing organelle volume. In turn, this affected ER Ca 2 þ release and cytosolic responses in HeLa cells. Most importantly, the modulation of mitochondrial Ca 2 þ uptake significantly reduced cellular sensitivity to the Ca 2 þ -mediated proapoptotic effect of C 2 ceramide. These results reveal a primary role of PGC-1a in shaping mitochondrial participation in calcium signalling, that underlies its protective role against stress and proapoptotic stimuli in pathophysiological conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1α

et al. 2005

View full text Add to dashboard Cite

show abstract

“…RyR2 and RyR3 are activated by Ca 2þ to greater extent than RyR1 and require higher Ca 2þ concentration for inactivation. Hence, at elevated cytoplasmic Ca 2þ concentrations Mg 2þ causes potent RyR1 inhibition and relatively little inhibition of RyR2 and RyR3 (Lamb 2000;Meissner 2002).…”

Section: Crystal Structure Of the Amino-terminal Domainmentioning

confidence: 99%

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Lanner¹,

Georgiou²,

Joshi³

et al. 2010

Cold Spring Harbor Perspectives in Biology

655

572

View full text Add to dashboard Cite

Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca 2þ from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (.2MDa) and exist as three mammalian isoforms (RyR 1 -3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.

show abstract

“…Ca 2+ and Mg 2+ titrations in [ 3 H]ryanodine binding and Ca 2+ release experiments have revealed Hill coefficients >1, indicating multiple, coordinated regulation of CICR channels by multiple cation binding sites [15]. Mg 2+ inhibition studied with channels reconstituted in lipid bilayer membranes [16] and Ca 2+ release from SR membrane vesicles [4] and [11] suggest dual mechanisms of Mg 2+ inhibition through competition with Ca 2+ for high affinity (H) activation sites and binding at low affinity (L) cation inhibition sites.…”

mentioning

confidence: 99%

Allosterically coupled calcium and magnesium binding sites are unmasked by ryanodine receptor chimeras

Voss

Allen

Pessah

et al. 2008

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

We studied cation regulation of wild type ryanodine receptor type 1 ( WT RyR1), type 3 ( WT RyR3) and RyR3/RyR1 chimeras (Ch) expressed in 1B5 dyspedic myotubes. Using [ 3 H]ryanodine binding to sarcoplasmic reticulum (SR) membranes, Ca 2+ titrations with WT RyR3 and three chimeras show biphasic activation that is allosterically coupled to attenuated inhibition relative to WT RyR1. Chimeras show biphasic Mg 2+ inhibition profiles at 3 and 10μM Ca 2+ , no observable inhibition at 20μM Ca 2+ and monophasic inhibition at 100μM Ca 2+ . Ca 2+ imaging of intact myotubes expressing Ch-4 exhibit caffeine-induced Ca 2+ transients with inhibition kinetics that are significantly slower than those expressing WT RyR1 or WT RyR3. Four new aspects of RyR regulation are evident: 1) high affinity (H) activation and low affinity (L) inhibition sites are allosterically coupled, 2) Ca 2+ facilitates removal of the inherent Mg 2+ block, 3) WT RyR3 exhibits reduced cooperativity between H activation sites when compared to WT RyR1, and 4) uncoupling of these sites in Ch-4 results in decreased rates of inactivation of caffeine-induced Ca transients.Keywords ryanodine receptors; calcium-induced calcium release; channel regulation Three isoforms of wild type ryanodine receptors ( WT RyR1, 2 and 3) are expressed in specialized regions of endoplasmic/sarcoplasmic reticulum (ER/SR) in most mammalian cells where they function as Ca 2+ Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Materials and Methods Chimeric RyR1/RyR3 constructsSpecific primers were designed for PCR amplification of the selected fragments using WT RyR1 as a template. Amplified fragments from WT RyR1 encoding aa 1681-2217 (Ch-17), 1924-2446 (Ch-21) and 1681-3770 (Ch-4) were inserted, in frame, into the endogenous restriction site(s) of HSV-RyR3 plasmid as described previously [20]. All chimeric constructs were cloned into the HSV-1 amplicon vector and packaged using a helper virus-free packaging system [22]. Cell culture, infection and membrane preparation1B5 myoblasts were cultured and differentiated into myotubes as described previously [20] and [23]. Plates with differentiated myotubes were infected with virion containing wild type and RyR1/RyR3 chimeric cDNA for 2 h and membrane extracts were prepared 36 h after infection. Myotubes were homogenized and membrane fractions obtained by differential centrifugation as described previously [24].[ cold buffer, placed into 5 ml scintillation cocktail (ScintiVerse; Fisher Scientific) and radioactivity counted. Equations for binding analysisCurve fitting was ...

show abstract

Regulation of mammalian ryanodine receptors

Cited by 163 publications

References 64 publications

Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1α

Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1α

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Allosterically coupled calcium and magnesium binding sites are unmasked by ryanodine receptor chimeras

Contact Info

Product

Resources

About