ライフサイエンスコーパス: RyR2

1 gated channels known as ryanodine receptors (RyR2).

2 ouse model expressing a GFP-tagged RyR2 (GFP-RyR2).

3 TPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2).

4 hythmias induced by a CaMKII-dependent leaky RyR2.

5 inding), with Ki > 10 mum, for both RyR1 and RyR2.

6 cance of the corresponding EF-hand domain in RyR2.

7 ential for dantrolene inhibition of RyR1 and RyR2.

8 e corresponding to the CaM-binding domain of RyR2.

9 ons not associated with CPVT can also affect RyR2.

10 in CPVT is not via a direct interaction with RyR2.

11 nal, but not cytosolic, Ca(2+) activation of RyR2.

12 ntify inhibitory mechanisms of flecainide on RyR2.

13 the expression of the calcium-handling gene Ryr2.

14 riers of the heterozygous mutation R4496C in RYR2.

15 eshold for SOICR leading to an inhibition of RyR2.

16 omoted by CaMKII phosphorylation of S2814 on RyR2.

17 modulates NaV1.5 and the ryanodine receptor, RyR2.

18 e EF-hand motifs on the Ca(2+) activation of RyR2.

19 dent protein kinase (CaMKII)-dependent leaky RyR2.

20 inding or the cytosolic Ca(2+) activation of RyR2.

21 eterminant of cytosolic Ca(2+) activation of RyR2.

22 The most common pathogenic mutations were RyR2 (2%), SCN5A (1%), and KNCQ1 (0.8%).

23 rs of the miR-106b-25 cluster, could bind to RyR2-3'-untranslated region and suppress its translation

24 ue in the S6 cytoplasmic region of the mouse RyR2 ((4876)QQEQVKEDM(4884)) and characterized their fun

25 Mutations in ryanodine receptor 2 (RyR2), a Ca(2+) release channel located in the sarcoplas

26 age of the increased nanotunnel frequency in RyR2(A4860G+/-) cardiomyocytes to investigate and accura

27 Mice heterozygous for the RyR2-A4860G mutation (RyR2-A4860G(+/-)) exhibited basal

28 terenol-stimulated ventricular myocytes, the RyR2-A4860G mutation decreased the peak of Ca(2+) releas

29 The RyR2-A4860G mutation reveals novel pathways by which RyR

30 Recombinant RyR2-A4860G protein was expressed equally as wild type (

31 timulation elicited malignant arrhythmias in RyR2-A4860G(+/-) hearts, recapitulating the phenotype or

32 e heterozygous for the RyR2-A4860G mutation (RyR2-A4860G(+/-)) exhibited basal bradycardia but no car

33 a mechanisms in a RyR2-linked CPVT mutation (RyR2-A4860G) that depresses channel activity.

34 Acute total Ryr2 ablation also impaired metabolism, but it was not c

35 d Ca(2+) release, but the molecular basis of RyR2 activation by cytosolic Ca(2+) is poorly defined.

36 hough the EF-hand domain is not required for RyR2 activation by cytosolic Ca(2+), it plays an importa

37 ty, whereas the fast block was unaffected by RyR2 activation.

38 Normal increases in RyR2 activity in response to increasing diastolic SR [Ca

39 DoxOL abolished the increase in RyR2 activity when luminal Ca(2+) was increased from 0.1

40 with the RyR2 complex shifts the increase in RyR2 activity with increasing luminal [Ca(2+)] away from

41 Using RyR2(ADA/+) knock-in mice, in which half of the CaM-RyR2

42 and stress-induced ventricular arrhythmia in RyR2(ADA/+) mice.

43 and NPPB and increases in MYH6, ATP2A2, PLN, RYR2, ADRA1A, ADRB1, MYL3, PDFKM, PDHX, and CPT1B.

44 approximately 3-fold increase) and unaltered RyR2 affinity for the FK506-binding protein FKBP12.6 (Kd

45 release through cardiac ryanodine receptors (RyR2) aggravate cardiac remodeling in mice carrying a hu

46 METHODS AND CPVT-associated genes RYR2 and CASQ2 variants were identified in one of the wo

47 ly, our results indicate that alterations of RyR2 and mitochondrial ROS generation form a vicious cyc

48 CR revealed that isolated ICC expressed both RyR2 and RyR3 subtypes.

49 doxorubicin and doxorubicinol interact with RyR2 and SERCA2A in similar ways, but that the metabolit

50 suppressed the luminal Ca(2+) activation of RyR2 and spontaneous Ca(2+) release in HEK293 cells duri

51 relationship of the NH2-terminal domains of RyR2 and the action of NH2-terminal disease mutations.

52 aturated C-domain is constitutively bound to RyR2 and the N-domain senses increases in Ca(2+) concent

53 s of direct blockade of ryanodine receptors (RyR2) and Na(+) channel inhibition.

54 Ca(2+) release channel (ryanodine receptor, RyR2), and it appears that attenuated CaM Ca(2+) binding

55 Ca(2+) release channel/ryanodine receptor 2 (RyR2), and mutations in CaM cause arrhythmias such as ca

56 biased toward the mitochondria-SR interface (RyR2), and this bias was promoted by Ca(2+) signaling ac

57 cytoplasmic region of S6 and the U motif of RyR2 are important for stabilizing the closed state of t

58 We show that RyR2 are oxidized in the atria of patients with chronic

59 understanding of CaM-dependent regulation of RyR2 as well as the mechanistic effects of arrhythmogeni

60 do-phosphorylation of the ryanodine receptor RyR2 at Ser2814 (S2814D(+/+) mice) exhibit a higher open

61 ure model, we detected a decrease in the CaM-RyR2 binding affinity (Kd approximately 51 nmol/L; appro

62 r potential binding targets and measured CaM-RyR2 binding affinity in situ (Kd=10-20 nmol/L).

63 A/+) knock-in mice, in which half of the CaM-RyR2 binding is suppressed, we estimated that >90% of Z-

64 eabilized myocytes, we specifically resolved RyR2-bound CaM from other potential binding targets and

65 e percentage of Z-line-localized CaM that is RyR2-bound, and test cellular function of defective CaM-

66 sed, we estimated that >90% of Z-line CaM is RyR2-bound.

67 additional inhibitory mechanism that reduces RyR2 burst duration.

68 ically depends not only on the expression of RyR2, but also on its distribution.

69 tein was expressed equally as wild type (WT) RyR2, but channel activity was dramatically inhibited, a

70 Our data demonstrate that leaky RyR2, but not IP3R2, channels cause mitochondrial Ca2+ o

71 y bind to and functionally modulate RyR1 and RyR2, but this does not involve direct competition at th

72 (store) Ca(2+), explaining the regulation of RyR2 by luminal Ca(2+), the initiation of Ca(2+) waves a

73 ned, this indicates that oxidation regulates RyR2 by the same mechanism as phosphorylation, methylxan

74 ctivation of the cardiac ryanodine receptor (RyR2) by elevating cytosolic Ca(2+) is a central step in

75 orylation of the cardiac ryanodine receptor (RyR2) by protein kinase A (PKA) at Ser-2808 is suggested

76 Targeting AF caused by leaky RyR2 Ca channels with R-propafenone may be a more mechan

77 to support the notion that flecainide blocks RyR2 Ca(2+) flux in the physiologically relevant (lumina

78 Thus, these results suggest that neuronal RyR2 Ca(2+) leak due to Calstabin2 deletion contributes

79 ide novel clues on how to suppress excessive RyR2 Ca(2+) release by manipulating the CaM-RyR2 interac

80 aM binds to and inhibits ryanodine receptor (RyR2) Ca release channels in the heart, but whether arrh

81 associated with leaky ryanodine receptor 2 (RyR2) Ca release channels.

82 Cardiac ryanodine receptor (Ryr2) Ca(2+) release channels and cellular metabolism ar

83 to mutations in cardiac ryanodine receptors (RyR2), calsequestrin, or calmodulin.

84 stinct interaction between CaM-F142L and the RyR2 CaMBD, which may explain the stronger CaM-dependent

85 in cardiomyocytes, and dissociating CaM from RyR2 can cause severe ventricular arrhythmia.

86 ions in the cardiac Ryanodine Receptor gene (RYR2) cause dominant catecholaminergic polymorphic ventr

87 e found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutat

88 ation induces Ca(2+) imbalance by depressing RyR2 channel activity during excitation-contraction coup

89 y" RyR2 channel, we exploited them to assess RyR2 channel function in beta cell dynamics.

90 Moreover, flecainide did not alter RyR2 channel gating and had negligible effect on the mec

91 his study, the large K(+) conductance of the RyR2 channel permits direct observation of blocking even

92 As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel f

93 in CREM mice normalized open probability of RyR2 channels and SR Ca(2+) release, delayed the develop

94 ain lethal arrhythmias in patients harboring RyR2 channels destabilized by loss-of-function mutations

95 Hence, hyperactive RyR2 channels eager to release Ca(2+) on their own appea

96 60G mutation reveals novel pathways by which RyR2 channels engage sarcolemmal currents to produce lif

97 Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of i

98 or inhibit SR Ca2+ leak, we found that leaky RyR2 channels result in mitochondrial Ca2+ overload, dys

99 The slow block was potentiated in RyR2 channels that had relatively low open probability,

100 [Ca(2+)], was duplicated by exposing native RyR2 channels to subphysiologic (</=1.0 microM) luminal

101 ular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondri

102 th drugs (0.01 muM-2.5 muM) activated single RyR2 channels, and this was reversed by drug washout.

103 tabilization of the binding of calstabin2 to RyR2 channels, which prevents Ca(2+) leakage, or blockin

104 olic and luminal Ca(2+) activation of single RyR2 channels.

105 ling, and altered Ca(2+) signaling via leaky RyR2 channels.

106 (2+) release via cardiac ryanodine receptor (RyR2) channels affected by gain-of-function mutations.

107 ytosolic Ca2+ signaling despite decreases in RyR2 cluster density and RyR2 protein expression.

108 lue (lambda1) of the adjacency matrix of the RyR2 cluster lattice.

109 e results by applying the model to realistic RyR2 cluster structures informed by super-resolution sti

110 Simultaneous detection of GFP-RyR2 clusters and Ca(2+) sparks showed that Ca(2+) spark

111 eal, for the first time, the distribution of RyR2 clusters and its functional correlation in living v

112 with colocalization of highly phosphorylated RyR2 clusters at AT-SR junctions and earlier, more rapid

113 Ca(2+) sparks from RyR2 clusters induced no detectable changes in mitochond

114 We also found GFP-RyR2 clusters interspersed between z-lines only at the p

115 Similar organization of GFP-RyR2 clusters was observed in fixed ventricular myocytes

116 ith di-8-ANEPPS revealed that nearly all GFP-RyR2 clusters were co-localized with transverse but not

117 (a z-line marker) showed that nearly all GFP-RyR2 clusters were localized in the z-line zone.

118 taining with MitoTracker Red showed that GFP-RyR2 clusters were not co-localized with mitochondria in

119 k model reveals functional subdomains within RyR2 clusters with distinct sensitivities to Ca2+.

120 There were small regions with dislocated GFP-RyR2 clusters.

121 at Ca(2+) sparks originated exclusively from RyR2 clusters.

122 ulum (SR) that include ryanodine receptor 2 (RyR2) clusters.

123 Accordingly, myospryn, minispryn and RyR2 co-localise at the junctional sarcoplasmic reticulu

124 Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for

125 sed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, C

126 ation, and lowered CSQ2 association with the RyR2 complex by 67%-77%.

127 tions: 1) [ROS] is produced locally near the RyR2 complex during X-ROS signaling and increases by an

128 ssociation of the monomeric protein with the RyR2 complex shifts the increase in RyR2 activity with i

129 nded entirely on the presence of CSQ2 in the RyR2 complex.

130 m Ca(2+)-leak via ryanodine receptor type-2 (RyR2) contributes to the pathogenesis of atrial fibrilla

131 These results demonstrate that Ryr2 controls mitochondrial Ca(2+) dynamics and plays a

132 articularly, the mutant Q4933A (or Q4863A in RyR2) critical for both the gating and Ryd binding not o

133 In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-c

134 e cellular level, flecainide did not inhibit RyR2-dependent sarcoplasmic reticulum Ca(2+) release.

135 mice expressing phosphorylation-incompetent RyR2 displayed depressed AM sarcomere shortening and red

136 that Zn(2+) is a high affinity regulator of RyR2 displaying three modes of operation.

137 s of dyads, enabling a direct examination of RYR2 distribution and arrangement.

138 The molecular mechanisms leading to RyR2 dysfunction and SR Ca(2+) leak depend on the clinic

139 RyR2 dysfunction causes increased diastolic SR Ca(2+) re

140 of intracellular Ca(2+) handling attenuates RyR2 dysfunction in CPVT.

141 , have implicated ryanodine receptor type 2 (RyR2) dysfunction and enhanced spontaneous Ca(2+) releas

142 f intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic pati

143 herapy target in AF associated with enhanced RyR2 expression.

144 yn and the major cardiac ryanodine receptor (RyR2) from heart.

145 al ryanodine receptors type I (RyR1) and II (RyR2) from skeletal and cardiac muscle, respectively.

146 but whether arrhythmogenic CaM mutants alter RyR2 function is not known.

147 These data show that the RyR2 gate directly senses luminal (store) Ca(2+), explai

148 the formation of Ca2+ sparks in terms of the RyR2 gating transition rates.

149 mics in cardiomyocytes through modulation of RyR2 gating.

150 ycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes

151 ction mutations in the ryanodine receptor-2 (RyR2) gene in both SUDEP and sudden cardiac death cases

152 knock-in mouse model expressing a GFP-tagged RyR2 (GFP-RyR2).

153 Here, we studied heart-specific, inducible Ryr2 haploinsufficient (cRyr2Delta50) mice with a stable

154 es 1-543) of the cardiac ryanodine receptor (RyR2) harbors a large number of mutations associated wit

155 (2+) leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity

156 sceptibility genes (KCNQ1, KCNH2, SCN5A, and RYR2) have yielded putative pathogenic mutations in </=3

157 heterozygous for the R4496C mutation in the RyR2) heterozygous CPVT mice.

158 ) mice) exhibit a higher open probability of RyR2, higher sarcoplasmic reticulum (SR) Ca(2+) leak in

159 tions in csq-1 (CASQ2 homologue) and unc-68 (RyR2 homologue).

160 ventricular tachycardia-susceptibility gene (RYR2) identified a putative pathogenic mutation in 11 ca

161 gh which these changes alter the activity of RyR2 in a cellular setting are poorly understood.

162 ion coupling; however, a functional role for RyR2 in beta cell insulin secretion and diabetes mellitu

163 he effects of the corresponding mutations in RyR2 in experiments.

164 To study the distribution of RyR2 in living cardiomyocytes, we generated a knock-in m

165 n about the distribution and organization of RyR2 in living cells.

166 n situ binding affinity and kinetics for CaM-RyR2 in normal and heart failure ventricular myocytes, e

167 studies identified a role of leaky neuronal RyR2 in posttraumatic stress disorder (PTSD).

168 onal coupling between L-type Ca channels and RyR2 in T3+Dex-treated cells.

169 lity of a Ca2+ spark occurring when a single RyR2 in the cluster opens spontaneously can be predicted

170 c ryanodine receptor Ca(2+) release channel (RyR2) in the sarcoplasmic reticulum (SR) membrane and th

171 lcium release channels (ryanodine receptors, RyR2) in the sarcoplasmic reticulum, and the frequency o

172 n, whereas deletion of the EF-hand domain of RyR2 increased both the activation and termination thres

173 urthermore, CaM-F142L enhanced CaM-dependent RyR2 inhibition at the single channel level compared wit

174 which may explain the stronger CaM-dependent RyR2 inhibition by CaM-F142L, despite its reduced Ca(2+)

175 Hence, multiple modes of action underlie RyR2 inhibition by flecainide.

176 ese two modes are independent mechanisms for RyR2 inhibition, both having a cytoplasmic site of actio

177 nding correlates with impaired CaM-dependent RyR2 inhibition.

178 and D130G, which all diminish CaM-dependent RyR2 inhibition.

179 Here, we investigated the RyR2 inhibitory action of the CaM p.Phe142Leu mutation (

180 Defective CaM-RyR2 interaction may occur in heart failure, cardiac hyp

181 A model for the CaM-RyR2 interaction, where the Ca(2+)-saturated C-domain is

182 and test cellular function of defective CaM-RyR2 interaction.

183 RyR2 Ca(2+) release by manipulating the CaM-RyR2 interaction.

184 tance of CPVT-CaM mutations and suggest that RyR2 interactions are unlikely to explain arrhythmogenic

185 en CaM and the CaM-binding domain (CaMBD) of RyR2 into an exothermal one.

186 Myospryn redistributes RyR2 into clusters when co-expressed in heterologous cel

187 Junctin, Junctate, Atp2a1, Atp11a, Cacna1s, Ryr2, intra and inter cellular transport, Clta, Stx2, Tj

188 -mediated post-transcriptional regulation of RyR2 is a potential molecular mechanism involved in paro

189 RyR2 is the major binding site for CaM along the Z-line

190 The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic retic

191 oxidation of the cardiac ryanodine receptor (RyR2) is known to activate and inhibit the channel depen

192 Recently, we demonstrated that total loss of Ryr2 leads to cardiomyocyte contractile dysfunction, arr

193 increased membrane excitability, and induced RyR2 leak.

194 production and pharmacological treatment of RyR2 leakage prevented AF.

195 imed to elucidate arrhythmia mechanisms in a RyR2-linked CPVT mutation (RyR2-A4860G) that depresses c

196 Our findings indicate that partial RYR2 loss is sufficient to cause metabolic abnormalities

197 RyR2 macromolecular complex remodeling, characterized by

198 d reduced posttranslational modifications of RyR2 macromolecular complex.

199 s a subunit of ryanodine receptor subtype 2 (RyR2) macromolecular complex, which is an intracellular

200 ice, suggesting that the reduction of mutant RyR2 may be a novel therapeutic approach for CPVT.

201 ns between CSQ2, triadin, and/or junctin and RyR2 may produce an arrhythmogenic substrate in anthracy

202 rome (D95V and D129G), or both (CaM N97S) on RyR2-mediated Ca(2+) release.

203 late current, but no effect on intracellular RyR2-mediated calcium release.

204 RyR2-mediated SR Ca(2+) leak directly underlies the deve

205 aM-F142L had little to no aberrant effect on RyR2-mediated store overload-induced Ca(2+) release in H

206 s developed that includes an X-ROS-dependent RyR2 mode switch.

207 To this end, a four-state RyR2 model was developed that includes an X-ROS-dependen

208 ations increased Ca(2+) release and rendered RyR2 more susceptible to store overload-induced Ca(2+) r

209 e ventricular myocytes isolated from the GFP-RyR2 mouse heart revealed clusters of GFP-RyR2 organized

210 -U10, the ratio between wild-type and mutant RYR2 mRNA was doubled (from 1:1 to 2:1) confirming the a

211 c polymorphic ventricular tachycardia-linked RyR2 mutation (A4860G) show a unique and unusual mitocho

212 Here we find that a human leaky RyR2 mutation, R176Q (RQ), alters neurotransmitter relea

213 ctional consequences of these central domain RyR2 mutations are not well understood.

214 vation of RyR2 represents a common defect of RyR2 mutations associated with CPVT and AF, which could

215 n HEK293 cells expressing the central domain RyR2 mutations associated with CPVT and AF.

216 We found that all eight central domain RyR2 mutations enhanced the Ca(2+)-dependent activation

217 d and characterized eight disease-associated RyR2 mutations in the central domain.

218 on to AF we used two murine models harboring RyR2 mutations that cause intracellular Ca(2+) leak.

219 Using murine models harboring RyR2 mutations that either cause or inhibit SR Ca2+ leak

220 Here, we took advantage of rare RyR2 mutations that were identified in patients with a g

221 to premature death in individuals with leaky RYR2 mutations.

222 4201) that contains a number of cardiac RyR (RyR2) mutations associated with catecholaminergic polymo

223 When activated, [Ca2+]i-sensitive RyR2 open probability increases, and the Ca2+ spark rate

224 stretching and subsequent ROS production on RyR2 open probability, Ca2+ sparks, and the myoplasmic c

225 to an increase in ryanodine receptor type 2 (RyR2) open probability by direct oxidation of the RyR2 p

226 is consistent with the RyR1 and cardiac RyR (RyR2) open-channel structures reported while this paper

227 Patients with mutations in RyR2 or in the sarcoplasmic reticulum Ca-binding protein

228 FP-RyR2 mouse heart revealed clusters of GFP-RyR2 organized in rows with a striated pattern.

229 erefore, our data suggest that low levels of RyR2 oxidation increase the channel activity by decreasi

230 threshold for SOICR, whereas high levels of RyR2 oxidation irreversibly increase the threshold for S

231 To dissect the molecular mechanism linking RyR2 oxidation to AF we used two murine models harboring

232 ease events was paralleled by an increase of RyR2 oxidation, but also by RyR-S2814 phosphorylation, a

233 This was not due to RyR2 oxidation, but depended entirely on the presence of

234 lular Ca(2+) leak exhibited increased atrial RyR2 oxidation, mitochondrial dysfunction, reactive oxyg

235 nt of rare predicted deleterious variants in RYR2 (p = 5 x 10(-5)).

236 or beta3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis i

237 rolonged cardiomyocyte action potentials and RyR2 phosphorylation (CamKII-dependent S2814) in the atr

238 ent study, we examined the potential role of RyR2 phosphorylation at Ser-2808 in the progression of C

239 ase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca

240 Ca(2+) release channel (ryanodine receptor, RyR2) plays an essential role in excitation-contraction

241 covered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretof

242 open probability by direct oxidation of the RyR2 protein complex.

243 espite decreases in RyR2 cluster density and RyR2 protein expression.

244 Total RyR2 protein in atrial tissue of miR-106b-25(-/-) mice w

245 Delta50) mice with a stable 50% reduction in Ryr2 protein.

246 marked increase in the highly phosphorylated RyR2-pS2808 cluster fraction, thereby maintaining cytoso

247 cardiac remodeling in mice carrying a human RyR2(R4496C+/-) gain-of-function mutation in response to

248 Wild-type and RyR2(R4496C+/-) hearts had comparable structural and fun

249 lymorphic ventricular tachycardia-associated RyR2(R4496C+/-) hearts were characterized under conditio

250 1 markedly reduced Ca(2+) spark frequency in RyR2(R4496C+/-)-TAC cardiomyocytes.

251 HF phenotype in RyR2(R4496C+/-)-TAC mice was associated with increased m

252 Using a CPVT mouse (RyR2(R4496C+/Cx40eGFP)), we tested whether PC intracellu

253 raperitoneal injection in neonatal and adult RyR2(R4496C/+) (mice heterozygous for the R4496C mutatio

254 their ability to selectively silence mutant RYR2-R4496C mRNA over the corresponding wild-type allele

255 ability of miRYR2-U10 to selectively inhibit RYR2-R4496C mRNA, whereas protein quantification showed

256 alogous to the established human CPVT mutant RyR2(R4497C), were unable to follow 3.7 Hz pacing, with

257 ions in the EF2 motif, but not EF1 motif, of RyR2 raised the threshold for SOICR termination, whereas

258 These results support aberrant RyR2 regulation as the disease mechanism for CPVT associ

259 teraction between CaM and the CaMBD and thus RyR2 regulation.

260 the effect of oxidation on a common form of RyR2 regulation; store overload-induced Ca(2+) release (

261 RyR2 remodeling in turn enhances betaAPP processing.

262 that altered cytosolic Ca(2+) activation of RyR2 represents a common defect of RyR2 mutations associ

263 zing the ryanodine receptors (RyRs; RyR1 and RyR2, respectively).

264 Each of these effects on CSQ2, and the lost RyR2 response to changes in luminal [Ca(2+)], was duplic

265 omolar free Zn(2+) concentrations potentiate RyR2 responses, but channel activation is still dependen

266 ce, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in

267 rface likely destabilize the closed state of RyR2, resulting in enhanced basal channel activity and s

268 pporting this notion, we found expression of RYR2 (Ryanodine Receptor 2) and SERCA2 further increased

269 r (AAV9) expressing miRYR2-U10 in correcting RyR2 (Ryanodine Receptor type 2 protein) function after

270 a release measured by Ca sparks and promoted RyR2 (ryanodine receptor) structural organization.

271 herefore, we explored the action of doxOL on RyR2's response to changes in luminal [Ca(2+)] seen duri

272 in kinase A-mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and l

273 modulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open

274 rotein kinase II (CaMKII) phosphorylation of RyR2-S2814 residue vs. normoglycaemia.

275 nodine binding and CaMKII phosphorylation of RyR2-S2814 residue vs. normoglycaemia.

276 e to CaMKII-dependent phosphorylation of the RyR2-S2814 site and underscore the benefits of increasin

277 nstitutive pseudo-phosphorylation at Ser2814-RyR2 (S2814D(+/+) ) have increased propensity to arrhyth

278 omyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3).

279 ibition of RyR1 (rabbit skeletal muscle) and RyR2 (sheep) with a maximal inhibition of Po (Emax) to 5

280 In heart failure, RyR2 shows decreased CaM affinity, but unaltered FKBP 12

281 CaMKII phosphorylation of RyR2, SR Ca(2+) leak and mitochondrial membrane depolari

282 RyR2-stabilizer K201 markedly reduced Ca(2+) spark frequ

283 f multiple RyRs and InsP3 Rs, with Itpr1 and Ryr2 subtypes displaying the highest expression.

284 attributable to partial dephosphorylation of RyR2 tetramers at Ser-2808 from more fully phosphorylate

285 The arrangement of RYR2 tetramers within the mammalian dyad is neither unif

286 is therefore a higher affinity activator of RyR2 than Ca(2+).

287 ) release via the type 2 ryanodine receptor (RyR2) that promotes AF.

288 pathway, there were 39 genes (i.e. CACNA1C, RyR2) that were associated with LAD, LVA and AF type.

289 oplasmic reticulum (SR) ryanodine receptors (RyR2) to the inner mitochondrial membrane (IMM) Ca(2+) u

290 , but native KCNE1 and ryanodine receptor 2 (RYR2) transcripts were unaffected.

291 Likewise, K201 activated cardiac RyR2 under systolic Ca(2+) conditions ( approximately 5

292 We report here that RyR2 undergoes post-translational modifications (phospho

293 asmic region in the function of cardiac RyR (RyR2) via structure-guided site-directed mutagenesis.

294 in which the CaMKII phosphorylation site on RyR2 was ablated.

295 eas protein quantification showed that total RyR2 was reduced by 15% in the heart of treated mice.

296 To localize the DPc10 binding site within RyR2, we measured FRET between five single-cysteine vari

297 RyR2 were isolated from sheep heart, incorporated into l

298 Itpr1 and Ryr2 were the dominant transcripts expressed by ICC.

299 Dantrolene inhibited RyR2 with an IC50 of 0.16 +/- 0.03 microM.

300 CaM binds to RyR2 with high affinity in cardiac myocytes.