scholarly journals A variably spliced region in the type 1 ryanodine receptor may participate in an inter-domain interaction

2006 ◽  
Vol 401 (1) ◽  
pp. 317-324 ◽  
Author(s):  
Takashi Kimura ◽  
Suzy M. Pace ◽  
Lan Wei ◽  
Nicole A. Beard ◽  
Robert T. Dirksen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Splice Variant ◽  
Synthetic Peptides ◽  
Channel Activity ◽  
Domain Interaction ◽  
Binding Partner ◽  
Binding Partners ◽  
Hypo Thesis

The aim of the present study was to examine residues that are variably spliced in the juvenile and adult isoforms of the skeletal-muscle RyR1 (type 1 ryanodine receptor). The juvenile ASI(−) splice variant is less active than the adult ASI(+) variant and is overexpressed in patients with DM (myotonic dystrophy) [Kimura, Nakamori, Lueck, Pouliquin, Aoike, Fujimura, Dirksen, Takahashi, Dulhunty and Sakoda (2005) Hum. Mol. Genet. 14, 2189–2200]. In the present study, we explore the ASI region using synthetic peptides corresponding to rabbit RyR1 residues Thr3471-Gly3500 either containing [PASI(+)] or lacking [PASI(−)] the ASI residues. Both peptides increased [3H]ryanodine binding to rabbit RyR1s, increased Ca2+ release from sarcoplasmic reti-culum vesicles and increased single RyR1 channel activity. The peptide PASI(−) was more active in each case than PASI(+). [3H]Ryanodine binding to recombinant ASI(+)RyR1 or ASI(−)-RyR1 was enhanced more by PASI(−) than PASI(+), with the greatest increase seen when PASI(−) was added to ASI(−)RyR1. The activation of the RyR channels is consistent with the hypo-thesis that the peptides interrupt an inhibitory inter-domain inter-action and that PASI(−) is more effective at interrupting this interaction than PASI(+). We therefore suggest that the ASI(−) sequence interacts more tightly than the ASI(+) sequence with its binding partner, so that the ASI(−)RyR1 is more strongly inhibited (less active) than the ASI(+)RyR1. Thus the affinity of the binding partners in this inter-domain interaction may deter-mine the activities of the mature and juvenile isoforms of RyR1 and the stronger inhibition in the juvenile isoform may contribute to the myopathy in DM.

scholarly journals Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1

2019 ◽  
Vol 170 (2) ◽  
pp. 509-524
Author(s):  
Kim M Truong ◽  
Gennady Cherednichenko ◽  
Isaac N Pessah
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Membrane Vesicles ◽  
Receptor Type ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Voltage Gated Sodium Channels ◽  
Muscle Health ◽  
Living Organisms

Abstract Dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) are ubiquitous in the environment and detected in tissues of living organisms. Although DDT owes its insecticidal activity to impeding closure of voltage-gated sodium channels, it mediates toxicity in mammals by acting as an endocrine disruptor (ED). Numerous studies demonstrate DDT/DDE to be EDs, but studies examining muscle-specific effects mediated by nonhormonal receptors in mammals are lacking. Therefore, we investigated whether o,p′-DDT, p,p′-DDT, o,p′-DDE, and p,p′-DDE (DDx, collectively) alter the function of ryanodine receptor type 1 (RyR1), a protein critical for skeletal muscle excitation-contraction coupling and muscle health. DDx (0.01–10 µM) elicited concentration-dependent increases in [3H]ryanodine ([3H]Ry) binding to RyR1 with o,p′-DDE showing highest potency and efficacy. DDx also showed sex differences in [3H]Ry-binding efficacy toward RyR1, where [3H]Ry-binding in female muscle preparations was greater than male counterparts. Measurements of Ca2+ transport across sarcoplasmic reticulum (SR) membrane vesicles further confirmed DDx can selectively engage with RyR1 to cause Ca2+ efflux from SR stores. DDx also disrupts RyR1-signaling in HEK293T cells stably expressing RyR1 (HEK-RyR1). Pretreatment with DDx (0.1–10 µM) for 100 s, 12 h, or 24 h significantly sensitized Ca2+-efflux triggered by RyR agonist caffeine in a concentration-dependent manner. o,p′-DDE (24 h; 1 µM) significantly increased Ca2+-transient amplitude from electrically stimulated mouse myotubes compared with control and displayed abnormal fatigability. In conclusion, our study demonstrates DDx can directly interact and modulate RyR1 conformation, thereby altering SR Ca2+-dynamics and sensitize RyR1-expressing cells to RyR1 activators, which may ultimately contribute to long-term impairments in muscle health.

scholarly journals Nicotinic acid–adenine dinucleotide phosphate activates the skeletal muscle ryanodine receptor

2002 ◽  
Vol 367 (2) ◽  
pp. 423-431 ◽  
Author(s):  
Martin HOHENEGGER ◽  
Josef SUKO ◽  
Regina GSCHEIDLINGER ◽  
Helmut DROBNY ◽  
Andreas ZIDAR
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Nicotinic Acid ◽  
Ryanodine Receptor ◽  
Spatial Information ◽  
Single Channel ◽  
Reversal Potential ◽  
Open Probability ◽  
Release Channel

Calcium is a universal second messenger. The temporal and spatial information that is encoded in Ca2+-transients drives processes as diverse as neurotransmitter secretion, axonal outgrowth, immune responses and muscle contraction. Ca2+-release from intracellular Ca2+ stores can be triggered by diffusible second messengers like InsP3, cyclic ADP-ribose or nicotinic acid—adenine dinucleotide phosphate (NAADP). A target has not yet been identified for the latter messenger. In the present study we show that nanomolar concentrations of NAADP trigger Ca2+-release from skeletal muscle sarcoplasmic reticulum. This was due to a direct action on the Ca2+-release channel/ryanodine receptor type-1, since in single channel recordings, NAADP increased the open probability of the purified channel protein. The effects of NAADP on Ca2+-release and open probability of the ryanodine receptor occurred over a similar concentration range (EC5030nM) and were specific because (i) they were blocked by Ruthenium Red and ryanodine, (ii) the precursor of NAADP, NADP, was ineffective at equimolar concentrations, (iii) NAADP did not affect the conductance and reversal potential of the ryanodine receptor. Finally, we also detected an ADP-ribosyl cyclase activity in the sarcoplasmic reticulum fraction of skeletal muscle. This enzyme was not only capable of synthesizing cyclic GDP-ribose but also NAADP, with an activity of 0.25nmol/mg/min. Thus, we conclude that NAADP is generated in the vicinity of type 1 ryanodine receptor and leads to activation of this ion channel.

scholarly journals Characterization of ryanodine receptor type 1 single channel activity using “on-nucleus” patch clamp

Cell Calcium ◽  
2014 ◽  
Vol 56 (2) ◽  
pp. 96-107 ◽  
Author(s):  
Larry E. Wagner ◽  
Linda A. Groom ◽  
Robert T. Dirksen ◽  
David I. Yule
Keyword(s):  
Patch Clamp ◽  
Ryanodine Receptor ◽  
Single Channel ◽  
Receptor Type ◽  
Channel Activity ◽  
Single Channel Activity

H2O2 and ethanol act synergistically to gate ryanodine receptor/calcium-release channel

2000 ◽  
Vol 279 (5) ◽  
pp. C1366-C1374 ◽  
Author(s):  
Toshiharu Oba ◽  
Tatsuya Ishikawa ◽  
Takashi Murayama ◽  
Yasuo Ogawa ◽  
Mamoru Yamaguchi
Keyword(s):  
Skeletal Muscle ◽  
Lipid Bilayers ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Physiological Role ◽  
Channel Activity ◽  
Calcium Release Channel ◽  
Open Probability ◽  
Skeletal Muscle Function ◽  
Release Channel

We examined the effect of low concentrations of H2O2 on the Ca2+-release channel/ryanodine receptor (RyR) to determine if H2O2 plays a physiological role in skeletal muscle function. Sarcoplasmic reticulum vesicles from frog skeletal muscle and type 1 RyRs (RyR1) purified from rabbit skeletal muscle were incorporated into lipid bilayers. Channel activity of the frog RyR was not affected by application of 4.4 mM (0.02%) ethanol. Open probability ( P o) of such ethanol-treated RyR channels was markedly increased on subsequent addition of 10 μM H2O2. Increase of H2O2to 100 μM caused a further increase in channel activity. Application of 4.4 mM ethanol to 10 μM H2O2-treated RyRs activated channel activity. Exposure to 10 or 100 μM H2O2 alone, however, failed to increase P o. Synergistic action of ethanol and H2O2 was also observed on the purified RyR1 channel, which was free from FK506 binding protein (FKBP12). H2O2 at 100–500 μM had no effect on purified channel activity. Application of FKBP12 to the purified RyR1 drastically decreased channel activity but did not alter the effects of ethanol and H2O2. These results suggest that H2O2 may play a pathophysiological, but probably not a physiological, role by directly acting on skeletal muscle RyRs in the presence of ethanol.

Treatment of Normal Skeletal Muscle with FK506 or Rapamycin Results in Halothane-induced Muscle Contracture

1998 ◽  
Vol 89 (3) ◽  
pp. 693-698. ◽  
Author(s):  
Richard L. Brooksbank ◽  
Margaret E. Badenhorts ◽  
Hyam Isaacs ◽  
Nerina Savage
Keyword(s):  
Carbon Dioxide ◽  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Human Skeletal Muscle ◽  
Receptor Type ◽  
Muscle Strip ◽  
Healthy Human ◽  
Healthy Persons

Background FKBP12 is a protein that is closely associated with the ryanodine receptor type 1 of skeletal muscle and modulates Ca2+ release by the channel. The immunosuppressants FK506 and rapamycin both bind to FKBP12 and in turn dissociate the protein from the ryanodine receptor. By treating healthy human skeletal muscle strips with FK506 or rapamycin and then subjecting the strips to the caffeine-halothane contracture test, this study determined that FK506 and rapamycin alter the sensitivity of the muscle strip to halothane, caffeine, or both. Methods Skeletal muscle strips from 10 healthy persons were incubated in Krebs medium equilibrated with a 95% oxygen and 5% carbon dioxide mixture, which contained either 12 microM FK506 (n = 8) or 12 microM rapamycin (n = 6), for 15 min at 37 degrees C. The strips were subjected to the caffeine-halothane contracture test for malignant hyperthermia according to the European Malignant Hyperthermia Group protocol. Results Treatment of normal skeletal muscle strips with FK506 and rapamycin resulted in halothane-induced contractures of 0.44+/-0.16 g and 0.6+/-0.49 g, respectively, at 2% halothane. Conclusions The results obtained show that pre-exposure of healthy skeletal muscle strips to either FK506 or rapamycin is sufficient to give rise to halothane-induced contractures. This is most likely caused by destabilization of Ca2+ release by the ryanodine receptor as a result of the dissociation of FKBP12. This finding suggests that a mutation in FKBP12 or changes in its capacity to bind to the ryanodine receptor could alter the halothane sensitivity of the skeletal muscle ryanodine receptor and thereby predispose the person to malignant hyperthermia.

Interaction of the Lys3614–Asn3643 calmodulin-binding domain with the Cys4114-Asn4142 region of the type 1 ryanodine receptor is involved in the mechanism of Ca2+/agonist-induced channel activation

2008 ◽  
Vol 411 (2) ◽  
pp. 415-423 ◽  
Author(s):  
Jaya P. Gangopadhyay ◽  
Noriaki Ikemoto
Keyword(s):  
Ryanodine Receptor ◽  
Binding Activity ◽  
Significant Inhibition ◽  
Binding Domain ◽  
Domain Pair ◽  
Dependent Manner ◽  
Domain Interaction ◽  
Channel Activation ◽  
Calmodulin Binding

In the present study we show that the interaction of the CaM (calmodulin)-binding domain (Lys3614–Asn3643) with the Cys4114–Asn4142 region (a region included in the CaM-like domain) serves as an intrinsic regulator of the RyR1 (type-1 ryanodine receptor). We tested the effects of antibodies raised against the two putative key regions of RyR1 [anti-(Lys3614–Asn3643) and anti-(Cys4114–Asn4142) antibodies]. Both antibodies produced significant inhibition of [3H]ryanodine-binding activity of RyR1. This suggests that the inter-domain interaction between the two domains, Lys3614–Asn3643 and Cys4114–Asn4142, activates the channel, and that the binding of antibody to either side of the interacting domain pair interfered with the formation of a ‘channel-activation link’ between the two regions. In order to spectroscopically monitor the mode of interaction of these domains, the site of inter-domain interaction was fluorescently labelled with MCA [(7-methoxycoumarin-4-yl)acetyl] in a site-directed manner. The accessibility of the bound MCA to a large molecular mass fluorescence quencher, BSA-QSY (namely, the size of a gap between the interacting domains) decreased with an increase of [Ca2+] in a range of 0.03–2.0 μM, as determined by Stern–Volmer fluorescence quenching analysis. The Ca2+-dependent decrease in the quencher accessibility was more pronounced in the presence of 150 μM 4-CmC (4-chlorometacresol), and was reversed by 1 mM Mg2+ (a well-known inhibitor of Ca2+/agonist-induced channel activation). These results suggest that the Lys3614–Asn3643 and Cys4114–Asn4142 regions of RyR1 interact with each other in a Ca2+- and agonist-dependent manner, and this serves as a mechanism of Ca2+- and agonist-dependent activation of the RyR1 Ca2+ channel.

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