ライフサイエンスコーパス: RyR1

1 ceptor and calcium (Ca(2+)) release channel (RyR1).

2 ease channel, the ryanodine receptor type 1 (RyR1).

3 een the DHPR and the Ca(2+) release channel (RyR1).

4 mutations within ryanodine receptor type 1 (RYR1).

5 mperature and the type I ryanodine receptor (RyR1).

6 e ryanodine receptor-Ca(2+)-release channel (RyR1).

7 hannels (CaV1.1) and the ryanodine receptor (RyR1).

8 the single-channel function of skeletal RyR (RyR1).

9 (CaV1.1) and the type 1 ryanodine receptor (RyR1).

10 r calcium channel type 1 ryanodine receptor (RyR1).

11 to that in myotubes, despite the absence of RyR1.

12 that FKBP12.6 activates and FKBP12 inhibits RyR1.

13 etween the C-terminal tail of the beta1a and RyR1.

14 l as stimulus-coupled Ca(2+) release through RyR1.

15 r conditions that altered the redox state of RyR1.

16 ural models of the open and closed states of RyR1.

17 ) or central (residues 2157-2777) regions of RyR1.

18 namer that binds the Ca(2+)-release channel, RyR1.

19 establish physical links between CaV1.1 and RyR1.

20 seems to be caused by an open state block of RyR1.

21 M, as opposed to direct effects of Ca(2+) on RyR1.

22 3 of arterioles and neither vessel expressed RyR1.

23 lease due to PKA phosphorylation of S2844 in RyR1.

24 iological role for oxidative modification of RyR1.

25 a Ca(2+) sensor that regulates the gating of RyR1.

26 ependent on different structural elements of RyR1.

27 n conformational coupling between CaV1.1 and RyR1.

28 the sarcoplasmic reticulum (SR) through the RyR1.

29 RyR1/2 protein immunoreactivity was detected in activate

30 RyR1/2 transcript levels increased, whereas those of RyR

31 on (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation that i

32 of RyR1 cysteine thiols results in increased RyR1 activity and Ca(2+) release in isolated sarcoplasmi

33 inding protein 12 subunit (FKBP12) increases RyR1 activity and impairs muscle function.

34 nishing S-palmitoylation directly suppresses RyR1 activity as well as stimulus-coupled Ca(2+) release

35 gh additive to) any indirect consequences to RyR1 activity that arise as a result of K(+) fluxes acro

36 in multiple functional domains implicated in RyR1 activity-regulating interactions with the L-type Ca

37 egligible effects on Ca(2+) release flux and RyR1 activity.

38 ion is strongly regulated by temperature and RyR1 activity.

39 ation converts MCa from positive to negative RyR1 allosteric modulator.

40 vides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD

41 Missense mutations resulting in 2 homozygous RYR1 amino acid substitutions (E989G and R3772W) and 2 c

42 ur open-channel model is consistent with the RyR1 and cardiac RyR (RyR2) open-channel structures repo

43 apping but distinct binding sites for CaM in RyR1 and imply that the binding location switch is due t

44 TBBPA activated RyR1 and inhibited DHPR and SERCA, inducing a net efflux

45 C-4/HDAC-5 exhibited decreased expression of RYR1 and of muscle-specific miRNAs, whereas acute knock-

46 l muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model

47 different effects of FKBP12 and FKBP12.6 on RyR1 and RyR2 channel gating provide scope for diversity

48 ncurrently bind to and functionally modulate RyR1 and RyR2, but this does not involve direct competit

49 y stabilizing the ryanodine receptors (RyRs; RyR1 and RyR2, respectively).

50 With respect to the functional regulation of RyR1 and RyR2, the FKBP12E31Q/D32N/W59F mutant lost all

51 .e. CaM binding), with Ki > 10 mum, for both RyR1 and RyR2.

52 aM is essential for dantrolene inhibition of RyR1 and RyR2.

53 in several genes including MTM1, DNM2, BIN1, RYR1 and TTN.

54 Ryanodine receptor types 1 (RyR1) and 2 (RyR2) are calcium release channels that are

55 EC) coupling, the type 1 ryanodine receptor (RyR1) and Ca(V)1.1, the principal subunit of the L-type

56 d labeling of the type 1 ryanodine receptor (RyR1) and fluorescence resonance energy transfer (FRET)

57 tact, functional ryanodine receptors type I (RyR1) and II (RyR2) from skeletal and cardiac muscle, re

58 Inhibitors of ryanodine receptors (RyR1) and L-type Ca(2+) channels protect voltage-induced

59 ells by expression of CaV1.1, beta1a, Stac3, RyR1, and junctophilin2.

60 Overall, RyR1 appears to cause a substantial reorientation of the

61 Mutations in RYR1 are associated with several congenital myopathies (

62 Mutations in skeletal muscle RyR (RyR1) are associated with congenital diseases such as ma

63 dine receptor (DHPR) and ryanodine receptor (RyR1) are known to engage a form of conformation couplin

64 Mutations in ryanodine receptor 1 (RyR1) are often associated with myopathies with microsco

65 from skeletal muscle sarcoplasmic reticulum (RyR1) are shown to be potent inhibitors of single-channe

66 Ca(2+) release channel, ryanodine receptor (RyR1), are essential for excitation-contraction coupling

67 of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention.

68 RYR1-associated myopathies should be included in the dif

69 hat is incapable of binding calcium binds to RyR1 at the apo site, regardless of the calcium concentr

70 oteins compete for the same binding sites on RyR1 because channels that are preactivated by FKBP12.6

71 raction that regulates the transition of the RyR1 between gating and leak states.

72 SR vesicles enriched in RyR1 bound approximately 48 [(3)H]S107 per RyR1 tetramer

73 We have also re-determined the location of RyR1-bound Ca(2+)-CaM using uniform experimental conditi

74 Apocalmodulin (apo-CaM) weakly activates RyR1 but inhibits RyR2, whereas Ca(2+)-calmodulin inhibi

75 FKBP12E31Q/D32N/W59F activated RyR1 but was not capable of activating RyR2.

76 g the activity of type 1 ryanodine receptor (RyR1), but its potential to influence physiological exci

77 indings demonstrate functional regulation of RyR1 by a previously unreported post-translational modif

78 odel suggested that luminal Ca(2+) activates RyR1 by accessing a recently identified cytosolic Ca(2+)

79 Thus, physiological redox regulation of RyR1 by endogenously generated hydrogen peroxide is exer

80 ) release channel/ryanodine receptor type 1 (RyR1) by protein kinase A (PKA) is critical for skeletal

81 rtebrates, this depends on activation of the RyR1 Ca(2+) pore in the SR, under control of conformatio

82 onsistent with mislocalization of Serca1 and Ryr1, calcium handling was drastically altered in Rbfox1

83 7, a small molecule drug that stabilizes the RyR1-calstabin1 interaction, prevented VIDD.

84 he ryanodine receptor/Ca(2+)-release channel RyR1 can be enhanced by S-oxidation or S-nitrosylation o

85 unctions and to test whether the presence of RyR1 caused altered FRET.

86 Association with RyR1 caused II-III loop FRET to decrease with the C term

87 cle fibers subjected to voltage-clamp and on RyR1 channel activity after incorporating sarcoplasmic r

88 1, its dioxole derivative, and 4-MmC inhibit RyR1 channel activity by virtue of their electron donor

89 beta1a490-508 also increased RyR1 channel activity in bilayers and Cav1.1 currents in

90 RyR1 channel activity is modulated by the beta1a subunit

91 feine stimulation, suggesting a reduction in RyR1 channel activity.

92 the central domain of the RyR1 that produces RyR1 channel destabilization.

93 ndicate that both glycines are important for RyR1 channel function by providing flexibility and minim

94 To better understand RyR1 channel function, we investigated the molecular mec

95 ines, Gly-4934 and Gly-4941, that facilitate RyR1 channel gating by providing S6 flexibility and mini

96 Pronounced abnormalities inherent in T4826I-RYR1 channels confer MHS and promote basal disturbances

97 We find that RyR1 channels from Tric-a KO mice respond normally to cy

98 The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracel

99 )'s and Sm(3+)'s action was tested on single RyR1 channels reconstituted into planar lipid bilayers.

100 IC-A functions as an excitatory modulator of RyR1 channels within the SR terminal cisternae.

101 endent of Ca(2+) store depletion or block of RyR1 channels.

102 This protein, FKBP12, promotes the RyR1 closed state, thereby inhibiting Ca(2+) leakage in

103 n of the skeletal muscle ryanodine receptor (RyR1) complex results in the rapid release of Ca(2+) fro

104 ation within the S4-S5 cytoplasmic linker of RYR1 confers genotype- and sex-dependent susceptibility

105 d then targeted these D-FKBPs to full-length RyR1 constructs containing decahistidine (His10) "tags"

106 ing involving cross-talk between IP(3)R1 and RyR1 contributes to Ca(2+) spark activation in skeletal

107 y, gene knockouts have revealed that CaV1.1/RyR1 coupling requires additional proteins, but leave op

108 mass spectrometry (yielding 93% coverage of RyR1 Cys residues) to identify 13 Cys residues subject t

109 d the consequent oxidation of a small set of RyR1 cysteine thiols results in increased RyR1 activity

110 that drugs that target ryanodine receptors (RyR1: dantrolene, tetracaine, S107) and L-type Ca(2+) ch

111 Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticul

112 ices were indistinguishable from those of WT RyR1, demonstrating our ability to modulate RyR1 gating

113 oteins affect the single-channel behavior of RyR1 derived from rabbit skeletal muscle.

114 otubes to provide evidence for an unexplored RyR1-DHPR interaction that regulates the transition of t

115 citation-contraction coupling and retrograde RyR1-DHPR signaling in isolated murine muscle fibers.

116 both orthograde E-C coupling and retrograde RyR1-DHPR signaling.

117 BPA and TBBPA on ryanodine receptor type 1 (RyR1), dihydropyridine receptor (DHPR), and sarcoplasmic

118 A RyR1 disease mutation, N760D, appears to directly impact

119 1 ryanodine receptor/Ca(2+) release channel (RyR1) display muscle weakness and atrophy, but the under

120 that Ca(V)1.1 functions not only to activate RyR1 during EC coupling, but also to suppress resting Ry

121 CE and also intracellular Ca(2+) release via RyR1 during skeletal muscle contraction.

122 In this study, we investigated whether the RyR1-E4242G mutation affects retrograde coupling.

123 activation kinetics of the L-type current in RyR1-E4242G myotubes resembled those of normal myotubes,

124 L-type current in myotubes homozygous for RyR1-E4242G was substantially reduced in amplitude ( app

125 tal myopathy harbored recessive mutations in RYR1, encoding the ryanodine receptor 1, and were suscep

126 Muscle membranes did not differ in RYR1 expression nor in Ser(2844) phosphorylation among t

127 In addition, a retrograde signal from the RyR1 facilitates gating of the voltage-gated calcium cha

128 S107 (a stabilizer of RyR1-FK506 binding protein coupling that reduces Ca(2+)

129 skeletal muscle function by stabilizing the RyR1-FKBP12 complex.

130 ed distinctly different binding locations on RyR1 for the two states of CaM.

131 wever, the same HIIT exercise does not cause RyR1 fragmentation in muscles of elite endurance athlete

132 usion, HIIT exercise induces a ROS-dependent RyR1 fragmentation in muscles of recreationally active s

133 performing the same HIIT exercise showed no RyR1 fragmentation or prolonged changes in the expressio

134 tive oxygen/nitrogen species (ROS)-dependent RyR1 fragmentation, calpain activation, increased SR Ca(

135 We find that RyR1 from Tric-a KO mice are more sensitive to inhibitio

136 Additionally, RyR1 from Tric-a KO mice are not activated by protein ki

137 of Mg(2+) , ATP cannot effectively activate RyR1 from Tric-a KO mice.

138 el required for skeletal muscle contraction; RyR1) from aged MCat mice was less oxidized, depleted of

139 Although the role of the EF-hand domain in RyR1 function has been studied extensively, little is kn

140 ) in the skeletal muscle ryanodine receptor (RyR1) functions as a Ca(2+) sensor that regulates the ga

141 rminant(s) for the physical link of DHPR and RyR1, further confirming a direct correspondence between

142 The role of RyR1-G4934 and -G4941 in the pore-lining helix in channe

143 and close times were observed between WT and RyR1-G4934A and -G4941A.

144 RyR1-G4934A had reduced K(+) conductance and ion selecti

145 RyR1-G4934A, -G4941A, and -G4941V mutant channels exhibi

146 Co-expression of RyR1-WT with RyR1-G4934V or -G4941I partially restored the WT phenoty

147 RyR1-G4941K did not fully close at nanomolar cytosolic C

148 Ca(2+)- and voltage-dependent regulation of RyR1-G4941K mutant channels was demonstrated.

149 We therefore investigated whether RyR1 gating behaviour is modified in the SR from Tric-a

150 The defective RyR1 gating that we describe probably contributes signif

151 RyR1, demonstrating our ability to modulate RyR1 gating without affecting ion permeation.

152 the hypothesis that this interface controls RyR1 gating, we designed mutations in the linker helix t

153 Mutations in the RYR1 gene cause severe myopathies.

154 The absence of high-resolution structures of RyR1 has limited our understanding of channel function a

155 ultiple caveolin-3 nonamers bind to a single RyR1 homotetramer.

156 ween recombinant cav-3 nonamers and purified RyR1 homotetramers that would imply that at least one of

157 Furthermore, in heterozygotes from the Ryr1(I4895T/WT) (IT/+) mouse line, carrying a knock-in m

158 reover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong

159 e sarcoplasmic reticulum proteins Serca1 and Ryr1 in a pattern indicative of colocalization with the

160 Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall

161 specific miRNAs, whereas acute knock-down of RYR1 in mouse muscle fibres by siRNA caused up-regulatio

162 uted widely within the cytoplasmic domain of RyR1 in multiple functional domains implicated in RyR1 a

163 Here, we present cryo-EM reconstructions of RyR1 in multiple functional states revealing the structu

164 S107 increased FKBP12 binding to RyR1 in SR vesicles in the presence of reduced glutathio

165 ) Ca(2+) release channel/ryanodine receptor (RyR1) in the diaphragm.

166 asma membrane and type 1 ryanodine receptor (RyR1) in the sarcoplasmic reticulum (SR) is thought to u

167 Ca(2+) release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR).

168 ) release via the type 1 ryanodine receptor (RyR1) in the sarcoplasmic reticulum (SR).

169 ates opening of the calcium release channel (RyR1) in the sarcoplasmic reticulum that supplies the ca

170 Rs interact with type 1 ryanodine receptors (RyR1) in the sarcoplasmic reticulum.

171 ar binding location to that of Ca(2+)-CaM on RyR1, in seeming agreement with the inhibitory effects o

172 from the SR and retrograde coupling by which RyR1 increases the magnitude of the Ca(2+) current via C

173 lts in an approximately 16 times more potent RyR1 inhibitor (IC(50) = 0.24 +/- 0.05 muM) compared wit

174 h the functional role of Stac3 in the CaV1.1-RyR1 interaction.

175 , which are thought to mediate direct beta1a-RyR1 interactions, weakened EC coupling but did not repl

176 from Tric-a KO mice by incorporating native RyR1 into planar phospholipid bilayers under voltage-cla

177 The skeletal muscle calcium release channel RyR1 is activated by Ca(2+)-free CaM and inhibited by Ca

178 S-Oxidation of RyR1 is coupled to muscle oxygen tension (pO2) through O

179 The ryanodine receptor ion channel RyR1 is present in skeletal muscle and has a large cytop

180 nature of how Stac3 acts on the DHPR and/or RyR1 is unknown.

181 The type-1 ryanodine receptor (RyR1) is an intracellular calcium (Ca(2+)) release chann

182 The type 1 ryanodine receptor (RyR1) is expressed widely in the brain, with high levels

183 predominant form of RyR in skeletal muscle, RyR1, is subject to Cys-directed modification by S-palmi

184 RyR2 are very similar to the skeletal muscle RyR1 isoform.

185 terozygous (Het) and homozygous (Hom) T4826I-RYR1 knock-in mice.

186 PT1 and MICU1), and 7 had variants in TTN or RYR1, large genes that are technically difficult to Sang

187 RyR1 leak functions are to keep [Ca(2+)](rest) and the S

188 turbation of Ca(V)1.1 negative regulation of RyR1 leak identifies a unique mechanism that can sensiti

189 Pharmacological control of the RyR1 leak state, using bastadin 5, reverted the three pa

190 We found that inhibiting RyR1 leakage, TGF-beta signaling, TGF-beta release from

191 2+) release in skeletal muscle by binding to RyR1 low affinity sites.

192 522S mutation causes greater openness of the RyR1, lowers resting [Ca2+]SR and alters SR Ca2+ bufferi

193 The RyR1 macromolecular complex was oxidized, S-nitrosylated

194 We found that in the absence of RyR1, measureable FRET occurred between the N terminus a

195 We show that ryanodine receptor 1 (Ryr1)-mediated Ca(2+) leak is an important mechanism for

196 other agents produced partial inhibition of RyR1-mediated Ca(2)(+) release from SR microsomes.

197 and that in its absence OSI causes increased RyR1-mediated Ca(2+) leak from the SR into the cytoplasm

198 ng EC coupling, but also to suppress resting RyR1-mediated Ca(2+) leak from the SR, and that perturba

199 K201 (>/=5 microM) increased RyR1-mediated Ca(2+) release from SkM microsomes.

200 ist) were found to significantly inhibit the RyR1-mediated caffeine-induced Ca(2)(+) release.

201 The type 1 ryanodine receptor (RyR1) mediates Ca(2+) release from the sarcoplasmic reti

202 Considering that both Het and Hom T4826I-RYR1 mice are viable, the remarkable isolated single cha

203 In this study, we identify a mouse RyR1 model in which heterozygous animals display clinica

204 To this end, we generated an open-channel RyR1 model using molecular simulations to pull Ca(2+) th

205 cles), an average of six to eight Cys thiols/RyR1 monomer are reversibly oxidized at high (21% O2) ve

206 ut their identity among the 100 Cys residues/RyR1 monomer is unknown.

207 Following purification, the RyR1 mutants G4934D, G4934K, and G4941D did not noticeab

208 Recent studies of RyR1 mutants, including the article by Bannister et al.

209 The RyR1 mutation decreases sensitivity to activated calcium

210 ossibly in humans carrying the corresponding RyR1 mutation.

211 ossibly in humans carrying the corresponding RyR1 mutation.

212 Patients carrying RYR1 mutations are at high risk of developing malignant

213 t muscle biopsies of patients with recessive RYR1 mutations exhibit decreased expression of muscle-sp

214 mmon feature of diseases caused by recessive RYR1 mutations is a decrease of ryanodine receptor 1 pro

215 e muscle damage of myopathies due to certain RyR1 mutations.

216 or heat-induced sudden death associated with RYR1 mutations.

217 plegia can result from ryanodine receptor 1 (RYR1) mutations without overt associated skeletal myopat

218 potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress.

219 These findings further imply that the RyR1 N-terminal and central domains are proximal to one

220 Expression of these constructs in dyspedic (RyR1 null) and dysgenic (alpha(1S) null) myotubes was us

221 d those of normal myotubes, unlike dyspedic (RyR1 null) myotubes in which the L-type currents have ma

222 ation was reduced threefold in myotubes from RyR1-null mice and increased 4.6-fold at physiological t

223 bility (Po) of very active ("high-activity") RyR1 of SkM reconstituted into bilayers, but it had no e

224 at use of ion-pulling simulations produces a RyR1 open-channel model, which can provide insights into

225 ticulum (SR) caused by missense mutations in RYR1 or CACNA1S, and the MH crisis has been attributed s

226 s consisting of residues 850-1,056 in rabbit RyR1 or residues 861-1,067 in mouse RyR2.

227 Exogenous expression of wild-type RyR1 partially restored L-type current density.

228 everal crystal structures of skeletal muscle RyR1 peptide fragments have been solved, but these cover

229 onist isoproterenol (isoprenaline) increased RyR1 PKA phosphorylation, twitch Ca(2+) and force genera

230 m these studies we draw two conclusions: (i) RyR1 plays a role in VICaR in hypothalamic nerve termina

231 From these studies we draw two (i) RyR1 plays a role in VICaR in hypothalamic nerve termina

232 Here we demonstrate that RyR1 plays a role in VICaR in nerve terminals.

233 Further, it suggests that the DHPR-uncoupled RyR1 population in WT muscle has a higher propensity to

234 The RyR1 pore architecture places it in the six-transmembran

235 g six transmembrane helices to calculate the RyR1 pore region conductance, to analyze its structural

236 ave reported a hypothetical structure of the RyR1 pore-forming region, obtained by homology modeling

237 d by a glycine for glutamate substitution at RyR1 position 4242.

238 blished, its binding determinants within the RyR1 protein sequence remain unresolved.

239 Here, we show in muscle cells from MH-RyR1(R163C) knock-in mice that increased passive SR Ca(2

240 sed, and [Na]i is chronically elevated in MH-RyR1(R163C) muscle cells.

241 ivo and further increased by halothane in MH-RyR1(R163C/WT) muscle.

242 + 2 mM ATP), dantrolene caused inhibition of RyR1 (rabbit skeletal muscle) and RyR2 (sheep) with a ma

243 nd were further evaluated with skeletal RyR (RyR1) reconstituted into planar bilayers.

244 an important pathophysiological mechanism in RYR1-related myopathies and that N-acetylcysteine is a s

245 xidative stress and improved survival in the RYR1-related myopathies human myotubes ex vivo and led t

246 d with several congenital myopathies (termed RYR1-related myopathies) that are the most common non-dy

247 sms, we analysed two complementary models of RYR1-related myopathies, the relatively relaxed zebrafis

248 While ophthalmoplegia occurs rarely in RYR1-related myopathies, these children were atypical be

249 ish and cultured myotubes from patients with RYR1-related myopathies.

250 e stress in relatively relaxed zebrafish and RYR1-related myopathy myotubes and demonstrated increase

251 Ryanodine receptor type 1 (RyR1) releases Ca(2+) from intracellular stores upon ner

252 nd mutations in the ryanodine receptor gene (RYR1) represent the most frequent cause of these conditi

253 -)menthol were found to inhibit and activate RyR1, respectively.

254 RyR1, RyR2, and RyR3 transcripts were detected in human

255 isoproterenol stimulation were abrogated in RyR1-S2844A mice in which the serine in the PKA site in

256 The RyR1 S6 pore-lining helix has two conserved glycines, Gl

257 e energy transfer (FRET) measurements to map RyR1 sequence elements forming the binding site of the 1

258 these cover less than 15% of the full-length RyR1 sequence.

259 inding motifs within the ryanodine receptor (RyR1) sequence employing a bioinformatic analysis.

260 nonessential role in the bidirectional DHPR/RyR1 signaling that supports skeletal-type EC coupling.

261 drugs with the aim of functionally modifying RyR1 single-channel activity.

262 ex of the rabbit skeletal muscle type 1 RyR (RyR1), solved by single-particle electron cryomicroscopy

263 e pore constriction site of a closed-channel RyR1 structure determined at 3.8-A resolution.

264 sites is exposed within the fully assembled RyR1 structure.

265 conclude that mutating residue E4242 affects RyR1 structures critical for retrograde communication wi

266 989G and R3772W) and 2 compound heterozygous RYR1 substitutions (H283R and R3772W) were identified in

267 into caveolin-3 assembly, interactions with RyR1 suggest a novel role in muscle contraction and/or f

268 Furthermore, a direct interaction with RyR1 suggests a possible role for cav-3 as a modifier of

269 The calculated conductance of the wild-type RyR1 suggests that the proposed pore structure can susta

270 ion T4825I in the type 1 ryanodine receptor (RYR1(T4825I/+)) confers human malignant hyperthermia sus

271 Heterozygous RYR1(T4826I/+) (Het) or homozygous RYR1(T4826I/T4826I) (

272 erozygous RYR1(T4826I/+) (Het) or homozygous RYR1(T4826I/T4826I) (Hom) mice are fully viable under ty

273 n RyR1 bound approximately 48 [(3)H]S107 per RyR1 tetramer with EC(50) approximately 52 microM and Hi

274 metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle.

275 Pro(2)(4)(7)(7) of the central domain of the RyR1 that produces RyR1 channel destabilization.

276 tion to the orthograde signal from CaV1.1 to RyR1 that triggers Ca(2+) release from the sarcoplasmic

277 mutations in the type 1 ryanodine receptor, RyR1, the Ca2+ channel of the sarcoplasmic reticulum (SR

278 y Nox4 governs the redox state of regulatory RyR1 thiols and thereby governs muscle performance.

279 pposed near the FKBP binding site within the RyR1 three-dimensional structure.

280 al to both N-terminal and central domains of RyR1, thus suggesting that the FKBP binding site is comp

281 plasmic reticulum, retrograde signaling from RyR1 to CaV1.1 results in increased amplitude and slowed

282 identified action of the compound on mutant Ryr1 to reduce Ca(2+) leak from the sarcoplasmic reticul

283 ightly controls gating of the pore domain of RyR1 to release Ca(2+).

284 st specific negative allosteric modulator of RyR1, to our knowledge, and represents a lead compound f

285 In contrast, wildtype RyR1 was closed and not activated by luminal Ca(2+) at l

286 Reduced RyR1 was greater than that of RyR3.

287 mice in which the serine in the PKA site in RyR1 was replaced with alanine.

288 sing overlapping peptides tested on isolated RyR1, we hypothesized that a 19-amino-acid residue pepti

289 The effects of S107 and FKBP12 on RyR1 were examined under conditions that altered the red

290 These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by

291 reconstructions of open and closed states of RyR1 were obtained from the same sample, enabling analys

292 reased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann

293 Mutations in RYR1 were the most common cause of congenital myopathies

294 In conclusion, FKBP12.6 activates RyR1, whereas FKBP12 activates RyR2 and this selective a

295 within the N-terminal, cytoplasmic region of RyR1, which are clustered in multiple functional domains

296 (4892)AGGG-F(4921) residues in the cavity of RyR1, which explain the effects of the corresponding mut

297 evidence that designing new drugs to target RyR1 with enhanced electron donor characteristics result

298 ty-governing protein-protein interactions of RyR1 with the L-type Ca(2+) channel CaV1.1, calmodulin,

299 Co-expression of RyR1-WT with RyR1-G4934V or -G4941I partially restored t

300 nd 37 degrees C) was observed in fibers from RYR1(Y522S/WT) mice, a mouse model of malignant hyperthe