scholarly journals Malignant hyperthermia mutation sites in the Leu2442–Pro2477 (DP4) region of RyR1 (ryanodine receptor 1) are clustered in a structurally and functionally definable area

2006 ◽  
Vol 401 (1) ◽  
pp. 333-339 ◽  
Author(s):  
Mark L. Bannister ◽  
Tomoyo Hamada ◽  
Takashi Murayama ◽  
Peta J. Harvey ◽  
Marco G. Casarotto ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Structural Studies ◽  
Amino Acid Residues ◽  
Domain Interaction ◽  
Closed State ◽  
Interdomain Interaction ◽  
Ryanodine Receptor 1 ◽  
Domain Peptide ◽  
Interdomain Interactions

To explain the mechanism of pathogenesis of channel disorder in MH (malignant hyperthermia), we have proposed a model in which tight interactions between the N-terminal and central domains of RyR1 (ryanodine receptor 1) stabilize the closed state of the channel, but mutation in these domains weakens the interdomain interaction and destabilizes the channel. DP4 (domain peptide 4), a peptide corresponding to residues Leu2442–Pro2477 of the central domain, also weakens the domain interaction and produces MH-like channel destabilization, whereas an MH mutation (R2458C) in DP4 abolishes these effects. Thus DP4 and its mutants serve as excellent tools for structure–function studies. Other MH mutations have been reported in the literature involving three other amino acid residues in the DP4 region (Arg2452, Ile2453 and Arg2454). In the present paper we investigated the activity of several mutants of DP4 at these three residues. The ability to activate ryanodine binding or to effect Ca2+ release was severely diminished for each of the MH mutants. Other substitutions were less effective. Structural studies, using NMR analysis, revealed that the peptide has two α-helical regions. It is apparent that the MH mutations are clustered at the C-terminal end of the first helix. The data in the present paper indicates that mutation of residues in this region disrupts the interdomain interactions that stabilize the closed state of the channel.

Effects of a domain peptide of the ryanodine receptor on Ca2+ release in skinned skeletal muscle fibers

2001 ◽  
Vol 281 (1) ◽  
pp. C207-C214 ◽  
Author(s):  
Graham D. Lamb ◽  
Giuseppe S. Posterino ◽  
Takeshi Yamamoto ◽  
Noriaki Ikemoto
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Coupling Mechanism ◽  
Force Response ◽  
Transverse Tubular System ◽  
Closed State ◽  
Ionic Substitution ◽  
Tubular System ◽  
Domain Peptide ◽  
Interdomain Interactions

Mutations in the central domain of the skeletal muscle ryanodine receptor (RyR) cause malignant hyperthermia (MH). A synthetic peptide (DP4) in this domain (Leu-2442–Pro-2477) produces enhanced ryanodine binding and sensitized Ca2+ release in isolated sarcoplasmic reticulum, similar to the properties in MH, possibly because the peptide disrupts the normal interdomain interactions that stabilize the closed state of the RyR (Yamamoto T, El-Hayek R, and Ikemoto N. J Biol Chem 275: 11618–11625, 2000). Here, DP4 was applied to mechanically skinned fibers of rat muscle that had the normal excitation-contraction coupling mechanism still functional to determine whether muscle fiber responsiveness was enhanced. DP4 (100 μM) substantially potentiated the Ca2+release and force response to caffeine (8 mM) and to low [Mg2+] (0.2 mM) in every fiber examined, with no significant effect on the properties of the contractile apparatus. DP4 also potentiated the response to submaximal depolarization of the transverse tubular system by ionic substitution. Importantly, DP4 did not significantly alter the size of the twitch response elicited by action potential stimulation. These results support the proposal that DP4 causes an MH-like aberration in RyR function and are consistent with the voltage sensor triggering Ca2+ release by destabilizing the closed state of the RyRs.

Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia

2004 ◽  
Vol 30 (3) ◽  
pp. 356-365 ◽  
Author(s):  
Monica Aleman ◽  
Joyce Riehl ◽  
Brian M. Aldridge ◽  
Richard A. Lecouteur ◽  
Jeffrey L. Stott ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Ryanodine Receptor 1

scholarly journals Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia

2017 ◽  
Vol 4 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Remai Parker ◽  
Anja H. Schiemann ◽  
Elaine Langton ◽  
Terasa Bulger ◽  
Neil Pollock ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Functional Characterization ◽  
Central Core ◽  
Central Core Disease ◽  
Ryanodine Receptor 1

Abstract 944: Tight Binding Of Calmodulin To The Cardiac Ryanodine Receptor May Reduce The Spontaneous Ca 2+ Release Events Induced By Mutation-linked, Defective Inter-domain Interaction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Xiaojuan Xu ◽  
Masafumi Yano ◽  
Makoto Ohno ◽  
Hitoshi Uchinoumi ◽  
Hiroki Tateishi ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Release Kinetics ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Critical Role ◽  
Polymorphic Ventricular Tachycardia ◽  
Fluorescence Labeling ◽  
Domain Interaction ◽  
Human Mutation ◽  
Domain Peptide ◽  
Cardiac Ryanodine Receptor

Interaction between N-terminal 1– 600 and central domains 2000 –2500 of ryanodine receptor (RyR2), where many mutations have been found in patients with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVC2) or catecholaminergic polymorphic ventricular tachycardia (CPVT), was recently found to play a critical role in channel regulation. Using the domain peptide approach, here, we investigated the role of calmodulin (CaM), one of the accessory proteins of the cardiac ryanodine receptor (RyR2), on Ca 2+ release kinetics. Sarcoplasmic reticulum (SR) vesicles were isolated from dog LV muscles (n=4), then RyR2 was fluorescently labeled with methylcoumarin acetate (MCA) using DP 163–195 , which harbors a human mutation site in ARVC (R176Q), as a site-directing carrier. DP 163–195 mediated a specific MCA fluorescence labeling of central domain (60Kd) of RyR2. Addition of DP 163–195 to the MCA-labeled SR competitively induced the domain unzipping between N-terminal and central domains, as evidenced by an increased accessibility of the bound MCA to a large-size fluorescence quencher. In saponin-permeabilized cardiomyocytes, the addition of DP 163–195 markedly increased the frequency of Ca 2+ sparks (SpF; s −1 ·100μm −1 :13.1±0.9, p<0.01), compared with normal cells (6.9±0.3). Addition of recombinant CaM (100nM), in the presence of KN-93 (CaMKII inhibitor), inhibited the DP 163–195 -induced increase in SpF (7.2±0.5, p<0.01). This effect of CaM was, however, abolished by co-addition of the antibody against the binding site of CaM within RyR2 (3583–3603) (SpF:12.9±0.7, p=ns), strongly suggesting that the binding of CaM to RyR2 corrects the abnormal Ca 2+ release induced by DP 163–195 . The mutation made in the domain peptide, mimicking the same human mutation in ARVC (R176Q) abolished all of the effects that would have been produced by DP 163–195 . In conclusion, the mutation-linked defective inter-domain interaction between N-terminal and central domains within RyR2 (viz. domain unzipping) may increase spontaneous Ca 2+ release, perhaps by weakening CaM-binding to RyR2. Restored binding of CaM to RyR2 may correct defective channel gating of the mutant RyR2.

scholarly journals Postulated role of interdomain interaction between regions 1 and 2 within type 1 ryanodine receptor in the pathogenesis of porcine malignant hyperthermia

2007 ◽  
Vol 402 (2) ◽  
pp. 349-357 ◽  
Author(s):  
Takashi Murayama ◽  
Toshiharu Oba ◽  
Hiroshi Hara ◽  
Kikuo Wakebe ◽  
Noriaki Ikemoto ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Single Channel ◽  
Adenine Nucleotide ◽  
Underlying Mechanism ◽  
Mammalian Skeletal Muscle ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Fk506 Binding Protein ◽  
Interdomain Interaction

We have demonstrated recently that CICR (Ca2+-induced Ca2+ release) activity of RyR1 (ryanodine receptor 1) is held to a low level in mammalian skeletal muscle (‘suppression’ of the channel) and that this is largely caused by the interdomain interaction within RyR1 [Murayama, Oba, Kobayashi, Ikemoto and Ogawa (2005) Am. J. Physiol. Cell Physiol. 288, C1222–C1230]. To test the hypothesis that aberration of this suppression mechanism is involved in the development of channel dysfunctions in MH (malignant hyperthermia), we investigated properties of the RyR1 channels from normal and MHS (MH-susceptible) pig skeletal muscles with an Arg615→Cys mutation using [3H]ryanodine binding, single-channel recordings and SR (sarcoplasmic reticulum) Ca2+ release. The RyR1 channels from MHS muscle (RyR1MHS) showed enhanced CICR activity compared with those from the normal muscle (RyR1N), although there was little or no difference in the sensitivity to several ligands tested (Ca2+, Mg2+ and adenine nucleotide), nor in the FKBP12 (FK506-binding protein 12) regulation. DP4, a domain peptide matching the Leu2442–Pro2477 region of RyR1 which was reported to activate the Ca2+ channel by weakening the interdomain interaction, activated the RyR1N channel in a concentration-dependent manner, and the highest activity of the affected channel reached a level comparable with that of the RyR1MHS channel with no added peptide. The addition of DP4 to the RyR1MHS channel produced virtually no further effect on the channel activity. These results suggest that stimulation of the RyR1MHS channel caused by affected inter-domain interaction between regions 1 and 2 is an underlying mechanism for dysfunction of Ca2+ homoeostasis seen in the MH phenotype.

3,5-Di-t-butyl catechol is a potent human ryanodine receptor 1 activator, not suitable for the diagnosis of malignant hyperthermia susceptibility

2012 ◽  
Vol 66 (1) ◽  
pp. 80-87
Author(s):  
Caterina Lacava ◽  
Andrea Michalek-Sauberer ◽  
Birgit Kraft ◽  
Giampietro Sgaragli ◽  
Elisabeth Sipos ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Malignant Hyperthermia Susceptibility ◽  
Ryanodine Receptor 1

Postulated role of interdomain interactions within the type 1 ryanodine receptor in the low gain of Ca2+-induced Ca2+ release activity of mammalian skeletal muscle sarcoplasmic reticulum

2005 ◽  
Vol 288 (6) ◽  
pp. C1222-C1230 ◽  
Author(s):  
Takashi Murayama ◽  
Toshiharu Oba ◽  
Shigeki Kobayashi ◽  
Noriaki Ikemoto ◽  
Yasuo Ogawa
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Single Channel ◽  
Common Mechanism ◽  
Mammalian Skeletal Muscle ◽  
Selective Stabilization ◽  
Interdomain Interactions

Ryanodine receptor (RyR) type 1 (RyR1) exhibits a markedly lower gain of Ca2+-induced Ca2+ release (CICR) activity than RyR type 3 (RyR3) in the sarcoplasmic reticulum (SR) of mammalian skeletal muscle (selective stabilization of the RyR1 channel), and this reduction in the gain is largely eliminated using 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS). We have investigated whether the hypothesized interdomain interactions within RyR1 are involved in the selective stabilization of the channel using [3H]ryanodine binding, single-channel recordings, and Ca2+ release from the SR vesicles. Like CHAPS, domain peptide 4 (DP4, a synthetic peptide corresponding to the Leu2442-Pro2477 region of RyR1), which seems to destabilize the interdomain interactions, markedly stimulated RyR1 but not RyR3. Their activating effects were saturable and nonadditive. Dantrolene, a potent inhibitor of RyR1 used to treat malignant hyperthermia, reversed the effects of DP4 or CHAPS in an identical manner. These findings indicate that RyR1 is activated by DP4 and CHAPS through a common mechanism that is probably mediated by the interdomain interactions. DP4 greatly increased [3H]ryanodine binding to RyR1 with only minor alterations in the sensitivity to endogenous CICR modulators (Ca2+, Mg2+, and adenine nucleotide). However, DP4 sensitized RyR1 four- to six-fold to caffeine in the caffeine-induced Ca2+ release. Thus the gain of CICR activity critically determines the magnitude and threshold of Ca2+ release by drugs such as caffeine. These findings suggest that the low CICR gain of RyR1 is important in normal Ca2+ handling in skeletal muscle and that perturbation of this state may result in muscle diseases such as malignant hyperthermia.

Sign in / Sign up

Export Citation Format

Share Document