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Journal articles on the topic 'Ryanodine receptor type 2'

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Published: 10 December 2022

Last updated: 28 January 2023

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1

Kawai, Ryo, Tetsuro Horikoshi, and Manabu Sakakibara. "Involvement of the Ryanodine Receptor in Morphologic Modification of Hermissenda Type B Photoreceptors After In Vitro Conditioning." Journal of Neurophysiology 91, no. 2 (February 2004): 728–35. http://dx.doi.org/10.1152/jn.00757.2003.

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We examined whether Ca2+ induced Ca2+ release through ryanodine receptors is involved in the conditioning of specific morphologic changes at the axon terminals of type B photoreceptors in the isolated circumesophageal ganglion of Hermissenda. Calcium chelation by bis(2-aminophenoxy) ethane- N,N,N′, N′-tetraacetic acid prevented the conformational change at the terminals after five paired presentations of light and vibration, which produce terminal branch contraction of B photoreceptors. Two ryanodine receptor blockers, dantrolene and micromolar concentrations of ryanodine, depressed the increase in excitability due to in vitro conditioning and the increase in intracellular Ca2+ in response to membrane depolarization. Although the ability to increase intracellular Ca2+ was depressed, synaptic transmission was preserved in the normal state from hair cells under dantrolene and ryanodine incubation. Ryanodine receptor blockers also prevented contraction at the B photoreceptor axon terminals. These results suggest that the ryanodine receptor has a crucial role in inducing the in vitro conditioning specific changes both physiologically and morphologically, including “focusing” at the B photoreceptor axon terminal.

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2

Chugun, Akihito, Osamu Sato, Hiroshi Takeshima, and Yasuo Ogawa. "Mg2+ activates the ryanodine receptor type 2 (RyR2) at intermediate Ca2+ concentrations." American Journal of Physiology-Cell Physiology 292, no. 1 (January 2007): C535—C544. http://dx.doi.org/10.1152/ajpcell.00275.2006.

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To clarify whether activity of the ryanodine receptor type 2 (RyR2) is reduced in the sarcoplasmic reticulum (SR) of cardiac muscle, as is the case with the ryanodine receptor type 1 (RyR1), Ca2+-dependent [3H]ryanodine binding, a biochemical measure of Ca2+-induced Ca2+ release (CICR), was determined using SR vesicle fractions isolated from rabbit and rat cardiac muscles. In the absence of an adenine nucleotide or caffeine, the rat SR showed a complicated Ca2+ dependence, instead of the well-documented biphasic dependence of the rabbit SR. In the rat SR, [3H]ryanodine binding initially increased as [Ca2+] increased, with a plateau in the range of 10–100 μM Ca2+, and thereafter further increased to an apparent peak around 1 mM Ca2+, followed by a decrease. In the presence of these modulators, this complicated dependence prevailed, irrespective of the source. Addition of 0.3–1 mM Mg2+ unexpectedly increased the binding two- to threefold and enhanced the affinity for [3H]ryanodine at 10–100 μM Ca2+, resulting in the well-known biphasic dependence. In other words, the partial suppression of RyR2 is relieved by Mg2+. Ca2+ could be a substitute for Mg2+. Mg2+ also amplifies the responses of RyR2 to inhibitory and stimulatory modulators. This stimulating effect of Mg2+ on RyR2 is entirely new, and is referred to as the third effect, in addition to the well-known dual inhibitory effects. This effect is critical to describe the role of RyR2 in excitation-contraction coupling of cardiac muscle, in view of the intracellular Mg2+ concentration.

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3

Takasawa, Shin, Michio Kuroki, Koji Nata, Naoya Noguchi, Takayuki Ikeda, Akiyo Yamauchi, Hiroyo Ota, et al. "A novel ryanodine receptor expressed in pancreatic islets by alternative splicing from type 2 ryanodine receptor gene." Biochemical and Biophysical Research Communications 397, no. 2 (June 2010): 140–45. http://dx.doi.org/10.1016/j.bbrc.2010.05.051.

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4

Ayabe, T., G. S. Kopf, and R. M. Schultz. "Regulation of mouse egg activation: presence of ryanodine receptors and effects of microinjected ryanodine and cyclic ADP ribose on uninseminated and inseminated eggs." Development 121, no. 7 (July 1, 1995): 2233–44. http://dx.doi.org/10.1242/dev.121.7.2233.

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Sperm-induced activation of mammalian eggs is associated with a transient increase in Ca2+ concentrations thought to be derived from inositol 1,4,5-trisphosphate-sensitive and -insensitive intracellular stores. Whereas the importance of inositol 1,4,5-trisphosphate-sensitive Ca2+ stores has been evaluated, the identity and role of inositol 1,4,5-trisphosphate-insensitive stores are poorly understood. To explore the role of the ryanodine-sensitive Ca2+ store, we first used reverse transcription-polymerase chain reaction to identify transcripts of the ryanodine receptor in eggs and determined that transcripts for the type 2 and 3 receptor were present. Immunoprecipitation of radioiodinated egg extracts with an antibody that recognizes both type 2 and 3 receptors detected specifically a band of Mr = 520,000. Immunolocalization of the receptor(s) using laser-scanning confocal microscopy revealed that the receptor(s) was uniformly distributed in the cortex of the germinal vesicle-intact oocyte, but became asymmetrically localized to the cortex in a region apposed to the meiotic spindle in the metaphase II-arrested egg; this asymmetrical localization developed by metaphase I. The role of the ryanodine receptor in mouse egg activation was examined by determining the effects of microinjected ryanodine or cyclic ADP ribose on endpoints of egg activation in either uninseminated or inseminated eggs. Ryanodine induced the conversion of the zona pellucida glycoprotein ZP2 to its postfertilization form ZP2f in a biphasic concentration-dependent manner; nanomolar concentrations stimulated this conversion, whereas micromolar concentrations had no stimulatory effect. Cyclic ADP ribose also promoted the ZP2 conversion, but with a hyperbolic concentration dependence. Neither of these compounds induced cell cycle resumption. Inhibiting the inositol 1,4,5-trisphosphate-sensitive Ca2+ store did not inhibit the ryanodine-induced ZP2 conversion and, reciprocally, inhibiting the ryanodine-sensitive Ca2+ store did not inhibit the inositol 1,4,5-trisphosphate-induced ZP2 conversion. Last, treatment of eggs under conditions that would block the release of Ca2+ from the ryanodine-sensitive store had no effect on any event of egg activation following fertilization. Results of these experiments suggest that although ryanodine receptors are present and functional, release of Ca2+ from this store is not essential for sperm-induced egg activation.

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5

Saeki, Kazuhiko, Ichiro Obi, Noriko Ogiku, Munekazu Shigekawa, Toshiaki Imagawa, and Takeshi Matsumoto. "Doxorubicin directly binds to the cardiac-type ryanodine receptor." Life Sciences 70, no. 20 (April 2002): 2377–89. http://dx.doi.org/10.1016/s0024-3205(02)01524-2.

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6

Coronado, R., J. Morrissette, M. Sukhareva, and D. M. Vaughan. "Structure and function of ryanodine receptors." American Journal of Physiology-Cell Physiology 266, no. 6 (June 1, 1994): C1485—C1504. http://dx.doi.org/10.1152/ajpcell.1994.266.6.c1485.

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Membrane depolarization, neurotransmitters, and hormones evoke a release of Ca2+ from intracellular Ca(2+)-storing organelles like the endoplasmic reticulum and, in muscle, the sarcoplasmic reticulum (SR). In turn, the released Ca2+ serves to trigger a variety of cellular responses. The presence of Ca2+ pumps to replenish intracellular stores was described more than 20 years ago. The presence of Ca2+ channels, like the ryanodine receptor, which suddenly release the organelle-stored Ca2+, is a more recent finding. This review describes the progress made in the last five years on the structure, function, and regulation of the ryanodine receptor. Numerous reports have described the response of ryanodine receptors to cellular ions and metabolites, kinases and other proteins, and pharmacological agents. In many cases, comparative measurements have been made using Ca2+ fluxes in SR vesicles, single-channel recordings in planar bilayers, and radioligand binding assays using [3H]ryanodine. These techniques have helped to relate the activity of single ryanodine receptors to global changes in the SR Ca2+ permeability. Molecular information on functional domains within the primary structure of the ryanodine receptor is also available. There are at least three ryanodine receptor isoforms in various tissues. Some cells, such as amphibian muscle cells, express more than a single isoform. The diversity of ligands known to modulate gating and the diversity of tissues known to express the protein suggest that the ryanodine receptor has the potential to participate in many types of cell stimulus-Ca(2+)-release coupling mechanisms.

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7

Chiang, David Y., Satadru Lahiri, Guoliang Wang, Jason Karch, Meng C. Wang, Sung Y. Jung, Albert J. R. Heck, Arjen Scholten, and Xander H. T. Wehrens. "Phosphorylation-Dependent Interactome of Ryanodine Receptor Type 2 in the Heart." Proteomes 9, no. 2 (June 7, 2021): 27. http://dx.doi.org/10.3390/proteomes9020027.

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Hyperphosphorylation of the calcium release channel/ryanodine receptor type 2 (RyR2) at serine 2814 (S2814) is associated with multiple cardiac diseases including atrial fibrillation and heart failure. Despite recent advances, the molecular mechanisms driving pathological changes associated with RyR2 S2814 phosphorylation are still not well understood. Methods: Using affinity-purification coupled to mass spectrometry (AP-MS), we investigated the RyR2 interactome in ventricles from wild-type (WT) mice and two S2814 knock-in mutants: the unphosphorylated alanine mutant (S2814A) and hyperphosphorylated mimic aspartic acid mutant (S2814D). Western blots were used for validation. Results: In WT mouse ventricular lysates, we identified 22 proteins which were enriched with RyR2 pull-down relative to both IgG control and no antibody (beads-only) pull-downs. Parallel AP-MS using WT, S2814A, and S2814D mouse ventricles identified 72 proteins, with 20 being high confidence RyR2 interactors. Of these, 14 had an increase in their binding to RyR2 S2814A but a decrease in their binding to RyR2 S2814D. We independently validated three protein hits, Idh3b, Aifm1, and Cpt1b, as RyR2 interactors by western blots and showed that Aifm1 and Idh3b had significantly decreased binding to RyR2 S2814D compared to WT and S2814A, consistent with MS findings. Conclusion: By applying state-of-the-art proteomic approaches, we discovered a number of novel RyR2 interactors in the mouse heart. In addition, we found and defined specific alterations in the RyR2 interactome that were dependent on the phosphorylation status of RyR2 at S2814. These findings yield mechanistic insights into RyR2 regulation which may guide future drug designs.

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8

Kada, Gerald, Lynda Blayney, Anneliese Raab, Sidney Fleischer, Hansgeorg Schindler, F. Anthony Lai, and Peter Hinterdorfer. "Recognition Force Microscospy of Single Ryanodine Receptor Type 1 (RyR1)." Single Molecules 1, no. 2 (June 2000): 174. http://dx.doi.org/10.1002/1438-5171(200006)1:2<174::aid-simo174>3.0.co;2-g.

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9

Bare, Dan J., Claudia S. Kettlun, Mei Liang, Donald M. Bers, and Gregory A. Mignery. "Cardiac Type 2 Inositol 1,4,5-Trisphosphate Receptor." Journal of Biological Chemistry 280, no. 16 (February 13, 2005): 15912–20. http://dx.doi.org/10.1074/jbc.m414212200.

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The type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2) was identified previously as the predominant isoform in cardiac ventricular myocytes. Here we reported the subcellular localization of InsP3R2 to the cardiomyocyte nuclear envelope (NE). The other major known endo/sarcoplasmic reticulum calcium-release channel (ryanodine receptor) was not localized to the NE, indicating functional segregation of these channels and possibly a unique role for InsP3R2 in regulating nuclear calcium dynamics. Immunoprecipitation experiments revealed that the NE InsP3R2 associates with Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ), the major isoform expressed in cardiac myocytes. Recombinant InsP3R2 and CaMKIIδBalso co-immunoprecipitated after co-expression in COS-1 cells. Additionally, the amino-terminal 1078 amino acids of the InsP3R2 were sufficient for interaction with CaMKIIδBand associated upon mixing following separate expression. CaMKII can also phosphorylate InsP3R2, as demonstrated by32P labeling. Incorporation of CaMKII-treated InsP3R2 into planar lipid bilayers revealed that InsP3-mediated channel open probability is significantly reduced (∼11 times) by phosphorylation via CaMKII. We concluded that the InsP3R2 and CaMKIIδ likely represent two central components of a multiprotein signaling complex, and this raises the possibility that calcium release via InsP3R2 in the myocyte NE may activate local CaMKII signaling, which may feedback on InsP3R2 function.

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10

Costa, Roberta Ribeiro, Wamberto Antonio Varanda, and Celso Rodrigues Franci. "A calcium-induced calcium release mechanism supports luteinizing hormone-induced testosterone secretion in mouse Leydig cells." American Journal of Physiology-Cell Physiology 299, no. 2 (August 2010): C316—C323. http://dx.doi.org/10.1152/ajpcell.00521.2009.

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Leydig cells are responsible for the synthesis and secretion of testosterone, processes controlled by luteinizing hormone (LH). Binding of LH to a G protein-coupled receptor in the plasma membrane results in an increase in cAMP and in intracellular Ca2+ concentration ([Ca2+]i). Here we show, using immunofluorescence, that Leydig cells express ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs). Measurements of intracellular calcium changes using the fluorescent calcium-sensitive dye fluo-3 and confocal microscopy show that both types of receptors are involved in a calcium-induced calcium release (CICR) mechanism, which amplifies the initial Ca2+ influx through plasma membrane T-type calcium channels (CaV3). The RyRs and IP3Rs are functional, as judged from both their activation by caffeine and IP3 and block by ryanodine and 2-aminoethoxydiphenyl borate (2-APB), respectively. RyRs are the principal players involved in the release of Ca2+ from the endoplasmic reticulum, as evidenced by the fact that global Ca2+ changes evoked by LH are readily blocked by 100 μM ryanodine but not by 2-APB or xestospongin C. Finally, steroid production by Leydig cells is inhibited by ryanodine but not by 2-APB. These results not only broaden our understanding of the role played by calcium in Leydig cells but also show, for the first time, that RyRs have an important role in determining testosterone secretion by the testis.

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11

Huang, Tai-Qin, Monte S. Willis, and Gerhard Meissner. "IL-6/STAT3 signaling in mice with dysfunctional type-2 ryanodine receptor." JAK-STAT 4, no. 4 (October 2, 2015): e1158379. http://dx.doi.org/10.1080/21623996.2016.1158379.

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12

Fauconnier, Jérémy, Stéphanie Roberge, Nathalie Saint, and Alain Lacampagne. "Type 2 ryanodine receptor: A novel therapeutic target in myocardial ischemia/reperfusion." Pharmacology & Therapeutics 138, no. 3 (June 2013): 323–32. http://dx.doi.org/10.1016/j.pharmthera.2013.01.015.

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13

Guse, Andreas H., and Insa M. A. Wolf. "Ca 2+ microdomains, NAADP and type 1 ryanodine receptor in cell activation." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1863, no. 6 (June 2016): 1379–84. http://dx.doi.org/10.1016/j.bbamcr.2016.01.014.

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14

Kurebayashi, Nagomi, Takashi Murayama, Akira Uehara, Midori Yasukochi, and Takashi Sakurai. "Divergent Effects of Disease-Associated Mutations on Type 2 Ryanodine Receptor Channel." Biophysical Journal 106, no. 2 (January 2014): 108a. http://dx.doi.org/10.1016/j.bpj.2013.11.662.

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15

Tamura, Mai, Nagomi Kurebayashi, Takashi Murayama, Shuichi Mori, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Junji Suzuki, Kazunori Kanemaru, Masamitsu Iino, and Takashi Sakurai. "Search for Type 2 Ryanodine Receptor Inhibitor by Monitoring Endoplasmic Reticulum Ca2+." Biophysical Journal 114, no. 3 (February 2018): 116a. http://dx.doi.org/10.1016/j.bpj.2017.11.670.

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16

Murayama, Takashi, Toshiharu Oba, Eisaku Katayama, Hideto Oyamada, Katsuji Oguchi, Masakazu Kobayashi, Kazuyuki Otsuka, and Yasuo Ogawa. "Characterization of type 3 ryanodine receptor (RyR3) purified from rabbit diaphragm." Japanese Journal of Pharmacology 79 (1999): 134. http://dx.doi.org/10.1016/s0021-5198(19)34551-2.

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17

Akita, Tenpei, and Kenji Kuba. "Functional Triads Consisting of Ryanodine Receptors, Ca2+ Channels, and Ca2+-Activated K+ Channels in Bullfrog Sympathetic Neurons." Journal of General Physiology 116, no. 5 (October 30, 2000): 697–720. http://dx.doi.org/10.1085/jgp.116.5.697.

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Fluorescent ryanodine revealed the distribution of ryanodine receptors in the submembrane cytoplasm (less than a few micrometers) of cultured bullfrog sympathetic ganglion cells. Rises in cytosolic Ca2+ ([Ca2+]i) elicited by single or repetitive action potentials (APs) propagated at a high speed (150 μm/s) in constant amplitude and rate of rise in the cytoplasm bearing ryanodine receptors, and then in the slower, waning manner in the deeper region. Ryanodine (10 μM), a ryanodine receptor blocker (and/or a half opener), or thapsigargin (1–2 μM), a Ca2+-pump blocker, or ω-conotoxin GVIA (ω-CgTx, 1 μM), a N-type Ca2+ channel blocker, blocked the fast propagation, but did not affect the slower spread. Ca2+ entry thus triggered the regenerative activation of Ca2+-induced Ca2+ release (CICR) in the submembrane region, followed by buffered Ca2+ diffusion in the deeper cytoplasm. Computer simulation assuming Ca2+ release in the submembrane region reproduced the Ca2+ dynamics. Ryanodine or thapsigargin decreased the rate of spike repolarization of an AP to 80%, but not in the presence of iberiotoxin (IbTx, 100 nM), a BK-type Ca2+-activated K+ channel blocker, or ω-CgTx, both of which decreased the rate to 50%. The spike repolarization rate and the amplitude of a single AP-induced rise in [Ca2+]i gradually decreased to a plateau during repetition of APs at 50 Hz, but reduced less in the presence of ryanodine or thapsigargin. The amplitude of each of the [Ca2+]i rise correlated well with the reduction in the IbTx-sensitive component of spike repolarization. The apamin-sensitive SK-type Ca2+-activated K+ current, underlying the afterhyperpolarization of APs, increased during repetitive APs, decayed faster than the accompanying rise in [Ca2+]i, and was suppressed by CICR blockers. Thus, ryanodine receptors form a functional triad with N-type Ca2+ channels and BK channels, and a loose coupling with SK channels in bullfrog sympathetic neurons, plastically modulating AP.

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18

Kenyon, J. L., D. D. McKemy, J. A. Airey, and J. L. Sutko. "Interaction between ryanodine receptor function and sarcolemmal Ca2+ currents." American Journal of Physiology-Cell Physiology 269, no. 2 (August 1, 1995): C334—C340. http://dx.doi.org/10.1152/ajpcell.1995.269.2.c334.

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We used the whole cell voltage-clamp technique to investigate the effects of disruption of Ca2+ release from the sarcoplasmic reticulum (SR) on sarcolemmal Ca2+ currents of chick myotubes kept in culture for 7 or 8 days. Ca2+ currents were recorded in 145 mM tetraethylammonium chloride and 10 mM Ca2+ with pipettes containing cesium and 10 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. We found two components of Ca2+ current: 1) relatively large T-type currents that were activated near -50 mV and inactivated during 100-ms depolarizations to potentials positive to -60 mV (they were of similar magnitude in Ba2+ or Ca2+ and were insensitive to nifedipine) and 2) L-type currents that were activated near 0 mV and showed little or no inactivation during 100-ms depolarizations (they were larger when Ba2+ was the charge carrier and were blocked by 10 microM nifedipine). Addition of 1 or 100 microM ryanodine to the culture medium for 6-7 days caused a modest but significant increase in the L-type Ca2+ current density (pA/pF). Ryanodine (1 or 100 microM) exposure for 1-7 days reduced the T-type Ca2+ current density to < 10% of control. In contrast, exposure to 1 microM ryanodine for 0.5-3 h had no significant effect on either component of Ca2+ current. These data indicate that ryanodine has no direct action on Ca2+ currents in chick myotubes. However, disruption of SR Ca2+ release for > 24 h changes sarcolemmal Ca2+ channel expression or function.

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19

Scriven, David R., Anne Berit Johnsen, Parisa Asghari, Keng Chang Chou, and Edwin D. Moore. "Direct Visualization of Type 2 Ryanodine Receptors using dSTORM." Biophysical Journal 118, no. 3 (February 2020): 98a. http://dx.doi.org/10.1016/j.bpj.2019.11.697.

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20

Ye, Yanping, Kuihuan Jian, Jonathan H. Jaggar, Anna N. Bukiya, and Alex M. Dopico. "Type 2 ryanodine receptors are highly sensitive to alcohol." FEBS Letters 588, no. 9 (March 12, 2014): 1659–65. http://dx.doi.org/10.1016/j.febslet.2014.03.005.

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21

Tuvia, Shmuel, Mona Buhusi, Lydia Davis, Mary Reedy, and Vann Bennett. "Ankyrin-B Is Required for Intracellular Sorting of Structurally Diverse Ca2+ Homeostasis Proteins." Journal of Cell Biology 147, no. 5 (November 29, 1999): 995–1008. http://dx.doi.org/10.1083/jcb.147.5.995.

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This report describes a congenital myopathy and major loss of thymic lymphocytes in ankyrin-B (−/−) mice as well as dramatic alterations in intracellular localization of key components of the Ca2+ homeostasis machinery in ankyrin-B (−/−) striated muscle and thymus. The sacoplasmic reticulum (SR) and SR/T-tubule junctions are apparently preserved in a normal distribution in ankyrin-B (−/−) skeletal muscle based on electron microscopy and the presence of a normal pattern of triadin and dihydropyridine receptor. Therefore, the abnormal localization of SR/ER Ca ATPase (SERCA) and ryanodine receptors represents a defect in intracellular sorting of these proteins in skeletal muscle. Extrapolation of these observations suggests defective targeting as the basis for abnormal localization of ryanodine receptors, IP3 receptors and SERCA in heart, and of IP3 receptors in the thymus of ankyrin-B (−/−) mice. Mis-sorting of SERCA 2 and ryanodine receptor 2 in ankyrin-B (−/−) cardiomyocytes is rescued by expression of 220-kD ankyrin-B, demonstrating that lack of the 220-kD ankyrin-B polypeptide is the primary defect in these cells. Ankyrin-B is associated with intracellular vesicles, but is not colocalized with the bulk of SERCA 1 or ryanodine receptor type 1 in skeletal muscle. These data provide the first evidence of a physiological requirement for ankyrin-B in intracellular targeting of the calcium homeostasis machinery of striated muscle and immune system, and moreover, support a catalytic role that does not involve permanent stoichiometric complexes between ankyrin-B and targeted proteins. Ankyrin-B is a member of a family of adapter proteins implicated in restriction of diverse proteins to specialized plasma membrane domains. Similar mechanisms involving ankyrins may be essential for segregation of functionally defined proteins within specialized regions of the plasma membrane and within the Ca2+ homeostasis compartment of the ER.

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Peng, Wei, Huaizong Shen, Jianping Wu, Wenting Guo, Xiaojing Pan, Ruiwu Wang, S. R. Wayne Chen, and Nieng Yan. "Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2." Science 354, no. 6310 (September 22, 2016): aah5324. http://dx.doi.org/10.1126/science.aah5324.

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23

Díaz-Muñoz, Mauricio, Myrna A. R. Dent, Daniel Granados-Fuentes, Adam C. Hall, Arturo Hernández-Cruz, Mary E. Harrington, and Raúl Aguilar-Roblero. "Circadian modulation of the ryanodine receptor type 2 in the SCN of rodents." NeuroReport 10, no. 3 (February 1999): 481–86. http://dx.doi.org/10.1097/00001756-199902250-00007.

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24

Westhoff, Jens H., Sung-Yong Hwang, R. Scott Duncan, Fumiko Ozawa, Pompeo Volpe, Kaoru Inokuchi, and Peter Koulen. "Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling." Cell Calcium 34, no. 3 (September 2003): 261–69. http://dx.doi.org/10.1016/s0143-4160(03)00112-x.

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25

Klipp, Robert C., Na Li, Qiongling Wang, Tarah A. Word, Martha Sibrian-Vazquez, Robert M. Strongin, Xander H. T. Wehrens, and Jonathan J. Abramson. "EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2." Heart Rhythm 15, no. 4 (April 2018): 578–86. http://dx.doi.org/10.1016/j.hrthm.2017.12.017.

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26

Campbell, Hannah M., Ann P. Quick, Issam Abu-Taha, David Y. Chiang, Carlos F. Kramm, Tarah A. Word, Sören Brandenburg, et al. "Loss of SPEG Inhibitory Phosphorylation of Ryanodine Receptor Type-2 Promotes Atrial Fibrillation." Circulation 142, no. 12 (September 22, 2020): 1159–72. http://dx.doi.org/10.1161/circulationaha.120.045791.

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Background: Enhanced diastolic calcium (Ca 2+ ) release through ryanodine receptor type-2 (RyR2) has been implicated in atrial fibrillation (AF) promotion. Diastolic sarcoplasmic reticulum Ca 2+ leak is caused by increased RyR2 phosphorylation by PKA (protein kinase A) or CaMKII (Ca 2+ /calmodulin-dependent kinase-II) phosphorylation, or less dephosphorylation by protein phosphatases. However, considerable controversy remains regarding the molecular mechanisms underlying altered RyR2 function in AF. We thus aimed to determine the role of SPEG (striated muscle preferentially expressed protein kinase), a novel regulator of RyR2 phosphorylation, in AF pathogenesis. Methods: Western blotting was performed with right atrial biopsies from patients with paroxysmal AF. SPEG atrial knockout mice were generated using adeno-associated virus 9. In mice, AF inducibility was determined using intracardiac programmed electric stimulation, and diastolic Ca 2+ leak in atrial cardiomyocytes was assessed using confocal Ca 2+ imaging. Phosphoproteomics studies and Western blotting were used to measure RyR2 phosphorylation. To test the effects of RyR2-S2367 phosphorylation, knockin mice with an inactivated S2367 phosphorylation site (S2367A) and a constitutively activated S2367 residue (S2367D) were generated by using CRISPR-Cas9. Results: Western blotting revealed decreased SPEG protein levels in atrial biopsies from patients with paroxysmal AF in comparison with patients in sinus rhythm. SPEG atrial-specific knockout mice exhibited increased susceptibility to pacing-induced AF by programmed electric stimulation and enhanced Ca 2+ spark frequency in atrial cardiomyocytes with Ca 2+ imaging, establishing a causal role for decreased SPEG in AF pathogenesis. Phosphoproteomics in hearts from SPEG cardiomyocyte knockout mice identified RyR2-S2367 as a novel kinase substrate of SPEG. Western blotting demonstrated that RyR2-S2367 phosphorylation was also decreased in patients with paroxysmal AF. RyR2-S2367A mice exhibited an increased susceptibility to pacing-induced AF, and aberrant atrial sarcoplasmic reticulum Ca 2+ leak, as well. In contrast, RyR2-S2367D mice were resistant to pacing-induced AF. Conclusions: Unlike other kinases (PKA, CaMKII) that increase RyR2 activity, SPEG phosphorylation reduces RyR2-mediated sarcoplasmic reticulum Ca 2+ release. Reduced SPEG levels and RyR2-S2367 phosphorylation typified patients with paroxysmal AF. Studies in S2367 knockin mouse models showed a causal relationship between reduced S2367 phosphorylation and AF susceptibility. Thus, modulating SPEG activity and phosphorylation levels of the novel S2367 site on RyR2 may represent a novel target for AF treatment.

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27

Takeshima, H. "Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2." EMBO Journal 17, no. 12 (June 15, 1998): 3309–16. http://dx.doi.org/10.1093/emboj/17.12.3309.

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Liu, Yiwei, Maura Porta, Jia Qin, Jorge Ramos, Alma Nani, Thomas R. Shannon, and Michael Fill. "Flux regulation of cardiac ryanodine receptor channels." Journal of General Physiology 135, no. 1 (December 14, 2009): 15–27. http://dx.doi.org/10.1085/jgp.200910273.

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The cardiac type 2 ryanodine receptor (RYR2) is activated by Ca2+-induced Ca2+ release (CICR). The inherent positive feedback of CICR is well controlled in cells, but the nature of this control is debated. Here, we explore how the Ca2+ flux (lumen-to-cytosol) carried by an open RYR2 channel influences its own cytosolic Ca2+ regulatory sites as well as those on a neighboring channel. Both flux-dependent activation and inhibition of single channels were detected when there were super-physiological Ca2+ fluxes (>3 pA). Single-channel results indicate a pore inhibition site distance of 1.2 ± 0.16 nm and that the activation site on an open channel is shielded/protected from its own flux. Our results indicate that the Ca2+ flux mediated by an open RYR2 channel in cells (∼0.5 pA) is too small to substantially regulate (activate or inhibit) the channel carrying it, even though it is sufficient to activate a neighboring RYR2 channel.

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LEITE, M. Fatima, Jonathan A. DRANOFF, Ling GAO, and Michael H. NATHANSON. "Expression and subcellular localization of the ryanodine receptor in rat pancreatic acinar cells." Biochemical Journal 337, no. 2 (January 8, 1999): 305–9. http://dx.doi.org/10.1042/bj3370305.

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The ryanodine receptor (RyR) is the principal Ca2+-release channel in excitable cells, whereas the inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) is primarily responsible for Ca2+ release in non-excitable cells, including epithelia. RyR also is expressed in a number of non-excitable cell types, but is thought to serve as an auxiliary or alternative Ca2+-release pathway in those cells. Here we use reverse transcription PCR to show that a polarized epithelium, the pancreatic acinar cell, expresses the type 2, but not the type 1 or 3, isoform of RyR. We furthermore use immunochemistry to demonstrate that the type 2 RyR is distributed throughout the basolateral and, to a lesser extent, the apical region of the acinar cell, but is excluded from the trigger zone, where cytosolic Ca2+ signals originate in this cell type. Since propagation of Ca2+ waves in acinar cells is sensitive to ryanodine, caffeine and Ca2+, these findings suggest that Ca2+ waves in this cell type result from the co-ordinated release of Ca2+, first from InsP3Rs in the trigger zone, then from RyRs elsewhere in the cell. RyR may play a fundamental role in Ca2+ signalling in polarized epithelia, including for Ca2+ signals initiated by InsP3.

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DU, Guo Guang, Hideto OYAMADA, Vijay K. KHANNA, and David H. MacLENNAN. "Mutations to Gly2370, Gly2373 or Gly2375 in malignant hyperthermia domain 2 decrease caffeine and cresol sensitivity of the rabbit skeletal-muscle Ca2+-release channel (ryanodine receptor isoform 1)." Biochemical Journal 360, no. 1 (November 8, 2001): 97–105. http://dx.doi.org/10.1042/bj3600097.

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Mutations G2370A, G2372A, G2373A, G2375A, Y3937A, S3938A, G3939A and K3940A were made in two potential ATP-binding motifs (amino acids 2370–2375 and 3937–3940) in the Ca2+-release channel of skeletal-muscle sarcoplasmic reticulum (ryanodine receptor or RyR1). Activation of [3H]ryanodine binding by Ca2+, caffeine and ATP (adenosine 5′-[β,γ-methylene]triphosphate, AMP-PCP) was used as an assay for channel opening, since ryanodine binds only to open channels. Caffeine-sensitivity of channel opening was also assayed by caffeine-induced Ca2+ release in HEK-293 cells expressing wild-type and mutant channels. Equilibrium [3H]ryanodine-binding properties and EC50 values for Ca2+ activation of high-affinity [3H]ryanodine binding were similar between wild-type RyR1 and mutants. In the presence of 1mM AMP-PCP, Ca2+-activation curves were shifted to higher affinity and maximal binding was increased to a similar extent for wild-type RyR1 and mutants. ATP sensitivity of channel opening was also similar for wild-type and mutants. These observations apparently rule out sequences 2370–2375 and 3937–3940 as ATP-binding motifs. Caffeine or 4-chloro-m-cresol sensitivity, however, was decreased in mutants G2370A, G2373A and G2375A, whereas the other mutants retained normal sensitivity. Amino acids 2370–2375 lie within a sequence (amino acids 2163–2458) in which some eight RyR1 mutations have been associated with malignant hyperthermia and shown to be hypersensitive to caffeine and 4-chloro-m-cresol activation. By contrast, mutants G2370A, G2373A and G2375A are hyposensitive to caffeine and 4-chloro-m-cresol. Thus amino acids 2163–2458 form a regulatory domain (malignant hyperthermia regulatory domain 2) that regulates caffeine and 4-chloro-m-cresol sensitivity of RyR1.

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Szentandrássy, Norbert, Zsuzsanna É. Magyar, Judit Hevesi, Tamás Bányász, Péter P. Nánási, and János Almássy. "Therapeutic Approaches of Ryanodine Receptor-Associated Heart Diseases." International Journal of Molecular Sciences 23, no. 8 (April 18, 2022): 4435. http://dx.doi.org/10.3390/ijms23084435.

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Cardiac diseases are the leading causes of death, with a growing number of cases worldwide, posing a challenge for both healthcare and research. Therefore, the most relevant aim of cardiac research is to unravel the molecular pathomechanisms and identify new therapeutic targets. Cardiac ryanodine receptor (RyR2), the Ca2+ release channel of the sarcoplasmic reticulum, is believed to be a good therapeutic target in a group of certain heart diseases, collectively called cardiac ryanopathies. Ryanopathies are associated with the impaired function of the RyR, leading to heart diseases such as congestive heart failure (CHF), catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia type 2 (ARVD2), and calcium release deficiency syndrome (CRDS). The aim of the current review is to provide a short insight into the pathological mechanisms of ryanopathies and discuss the pharmacological approaches targeting RyR2.

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Arnáiz-Cot, Juan José, Brooke James Damon, Xiao-Hua Zhang, Lars Cleemann, Naohiro Yamaguchi, Gerhard Meissner, and Martin Morad. "Cardiac calcium signalling pathologies associated with defective calmodulin regulation of type 2 ryanodine receptor." Journal of Physiology 591, no. 17 (August 30, 2013): 4287–99. http://dx.doi.org/10.1113/jphysiol.2013.256123.

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Batiste, Suzanne M., Daniel J. Blackwell, Kyungsoo Kim, Dmytro O. Kryshtal, Nieves Gomez-Hurtado, Robyn T. Rebbeck, Razvan L. Cornea, Jeffrey N. Johnston, and Bjorn C. Knollmann. "Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic." Proceedings of the National Academy of Sciences 116, no. 11 (February 21, 2019): 4810–15. http://dx.doi.org/10.1073/pnas.1816685116.

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Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias in a variety of heart diseases and has also been implicated in neurodegenerative and seizure disorders, making RyR2 an attractive therapeutic target for drug development. Here we synthesized and investigated the fungal natural product and known insect RyR antagonist (−)-verticilide and several congeners to determine their activity against mammalian RyR2. Although the cyclooligomeric depsipeptide natural product (−)-verticilide had no effect, its nonnatural enantiomer [ent-(+)-verticilide] significantly reduced RyR2-mediated spontaneous Ca2+ leak both in cardiomyocytes from wild-type mouse and from a gene-targeted mouse model of Ca2+ leak-induced arrhythmias (Casq2−/−). ent-(+)-verticilide selectively inhibited RyR2-mediated Ca2+ leak and exhibited higher potency and a distinct mechanism of action compared with the pan-RyR inhibitors dantrolene and tetracaine and the antiarrhythmic drug flecainide. ent-(+)-verticilide prevented arrhythmogenic membrane depolarizations in cardiomyocytes without significant effects on the cardiac action potential and attenuated ventricular arrhythmia in catecholamine-challenged Casq2−/− mice. These findings indicate that ent-(+)-verticilide is a potent and selective inhibitor of RyR2-mediated diastolic Ca2+ leak, making it a molecular tool to investigate the therapeutic potential of targeting RyR2 hyperactivity in heart and brain pathologies. The enantiomer-specific activity and straightforward chemical synthesis of (unnatural) ent-(+)-verticilide provides a compelling argument to prioritize ent-natural product synthesis. Despite their general absence in nature, the enantiomers of natural products may harbor unprecedented activity, thereby leading to new scaffolds for probe and therapeutic development.

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Nishio, Hajime, Misa Iwata, and Koichi Suzuki. "Postmortem Molecular Screening for Cardiac Ryanodine Receptor Type 2 Mutations in Sudden Unexplained Death." Circulation Journal 70, no. 11 (2006): 1402–6. http://dx.doi.org/10.1253/circj.70.1402.

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35

Li, Ming, Aydin Tay, Gisela Beutner, Wenjun Ding, Shey-Shing Sheu, and Keshore Bidasee. "Increased Levels Of Type 2 Ryanodine Receptor (RyR2) In Rat Heart Mitochondria During Diabetes." Biophysical Journal 96, no. 3 (February 2009): 114a. http://dx.doi.org/10.1016/j.bpj.2008.12.499.

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36

Conklin, Matthew W., Chris A. Ahern, Paola Vallejo, Vincenzo Sorrentino, Hiroshi Takeshima, and Roberto Coronado. "Comparison of Ca2+ Sparks Produced Independently by Two Ryanodine Receptor Isoforms (Type 1 or Type 3)." Biophysical Journal 78, no. 4 (April 2000): 1777–85. http://dx.doi.org/10.1016/s0006-3495(00)76728-2.

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37

Yamaguchi, Naohiro, Asima Chakraborty, Daniel A. Pasek, Jeffery D. Molkentin, and Gerhard Meissner. "Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 6 (June 2011): H2187—H2195. http://dx.doi.org/10.1152/ajpheart.00719.2010.

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Mice with three amino acid mutations in the calmodulin binding domain of type-2 ryanodine receptor ion channel ( Ryr2 ADA/ADA mice) have impaired intracellular Ca2+ handling and cardiac hypertrophy with death at an early age. In this report, the role of signaling molecules implicated in cardiac hypertrophy of Ryr2 ADA/ADA mice was investigated. Calcineurin A-β (CNA-β) and nuclear factor of activated T cell (NFAT) signaling were monitored in mice carrying either luciferase transgene driven by NFAT-dependent promoter or knockout of CNA-β. NFAT transcriptional activity in Ryr2 ADA/ADA hearts was not markedly upregulated at embryonic day 16.5 compared with wild-type but significantly increased at postnatal days 1 and 10. Ablation of CNA-β extended the life span of Ryr2 ADA/ADA mice and enhanced cardiac function without improving sarcoplasmic reticulum Ca2+ handling or suppressing the expression of genes implicated in cardiac hypertrophy. Embryonic day 16.5 Ryr2 ADA/ADA mice had normal heart weights with no major changes in Akt1 and class II histone deacetylase phosphorylation and myocyte enhancer factor-2 activity. In contrast, phosphorylation levels of Erk1/2, p90 ribosomal S6 kinases (p90RSKs), and GSK-3β were increased in hearts of embryonic day 16.5 homozygous mutant mice. The results indicate that an impaired calmodulin regulation of RyR2 was neither associated with an altered CNA-β/NFAT, class II histone deacetylase (HDAC)/MEF2, nor Akt signaling in embryonic day 16.5 hearts; rather increased Erk1/2 and p90RSK phosphorylation levels likely leading to reduced GSK-3β activity were found to precede development of cardiac hypertrophy in mice expressing dysfunctional ryanodine receptor ion channel.

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Adachi-Akahane, S., L. Cleemann, and M. Morad. "Cross-signaling between L-type Ca2+ channels and ryanodine receptors in rat ventricular myocytes." Journal of General Physiology 108, no. 5 (November 1, 1996): 435–54. http://dx.doi.org/10.1085/jgp.108.5.435.

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Calcium-mediated cross-signaling between the dihydropyridine (DHP) receptor, ryanodine receptor, and Na(+)-Ca2+ exchanger was examined in single rat ventricular myocytes where the diffusion distance of Ca2+ was limited to < 50 nm by dialysis with high concentrations of Ca2+ buffers. Dialysis of the cell with 2 mM Ca(2+)- indicator dye, Fura-2, or 2 mM Fura-2 plus 14 mM EGTA decreased the magnitude of ICa-triggered intracellular Ca2+ transients (Cai-transients) from 500 to 20-100 nM and completely abolished contraction, even though the amount of Ca2+ released from the sarcoplasmic reticulum remained constant (approximately 140 microM). Inactivation kinetics of ICa in highly Ca(2+)-buffered cells was retarded when Ca2+ stores of the sarcoplasmic reticulum (SR) were depleted by caffeine applied 500 ms before activation of ICa, while inactivation was accelerated if caffeine-induced release coincided with the activation of ICa. Quantitative analysis of these data indicate that the rate of inactivation of ICa was linearly related to SR Ca(2+)-release and reduced by > 67% when release was absent. Thapsigargin, abolishing SR release, suppressed the effect of caffeine on the inactivation kinetics of ICa. Caffeine-triggered Ca(2+)-release, in the absence of Ca2+ entry through the Ca2+ channel (using Ba2+ as a charge carrier), caused rapid inactivation of the slowly decaying Ba2+ current. Since Ba2+ does not release Ca2+ but binds to Fura-2, it was possible to calibrate the fluorescence signals in terms of equivalent cation charge. Using this procedure, the amplification factor of ICa-induced Ca2+ release was found to be 17.6 +/- 1.1 (n = 4). The Na(+)-Ca2+ exchange current, activated by caffeine-induced Ca2+ release, was measured consistently in myocytes dialyzed with 0.2 but not with 2 mM Fura-2. Our results quantify Ca2+ signaling in cardiomyocytes and suggest the existence of a Ca2+ microdomain which includes the DHP/ ryanodine receptors complex, but excludes the Na(+)-Ca2+ exchanger. This microdomain appears to be fairly inaccessible to high concentrations of Ca2+ buffers.

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Lee, Eun Hui, J. Rafael Lopez, Jingzi Li, Feliciano Protasi, Isaac N. Pessah, Do Han Kim, and P. D. Allen. "Conformational coupling of DHPR and RyR1 in skeletal myotubes is influenced by long-range allosterism: evidence for a negative regulatory module." American Journal of Physiology-Cell Physiology 286, no. 1 (January 2004): C179—C189. http://dx.doi.org/10.1152/ajpcell.00176.2003.

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Four ryanodine receptor type 1 and 2 chimeras (R4, R9, R10, and R16) and their respective wild-type ryanodine receptors (type 1 and 2; wtRyR1 and wtRyR2) were expressed in dyspedic 1B5 to identify possible negative regulatory modules of the Ca2+release channel that are under the influence of the dihydropyridine receptor (DHPR). Responses of intact 1B5 myotubes expressing each construct to caffeine in the absence or presence of either La3+and Cd2+or the organic DHPR blocker nifedipine were determined by imaging single 1B5 myotubes loaded with fluo 4. The presence of La3+and Cd2+or nifedipine in the external medium at concentrations known to block Ca2+entry through the DHPRs significantly decreased the caffeine EC50of wtRyR1 (2.80 ± 0.12 to 0.83 ± 0.09 mM; P < 0.05). On the other hand, DHPR blockade did not significantly alter the caffeine EC50values of wtRyR2, chimeras R10 and R16, whereas the caffeine EC50values of chimeras R4 and R9 were significantly increased (1.27 ± 0.05 to 2.60 ± 0.16 mM, and 1.15 ± 0.03 to 2.11 ± 0.32 mM, respectively; P < 0.05). Despite the fact that all the chimeras form fully functional Ca2+release channels in situ, sarcoplasmic reticulum (SR) containing R4, R10, and R16 did not possess high-affinity binding of [3H]ryanodine regardless of Ca2+concentration. These results suggest the presence of an interaction between RyR1 and the DHPR, which is not present in RyR2, that contributes negative control of SR Ca2+release induced by direct agonists such as caffeine. Although we were unable to define the negative module using RyR1-RyR2 chimeras, they further demonstrated that the RyR is very sensitive to long-range allosterism.

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MACKRILL, John J., R. A. John CHALLISS, D. A. O'CONNELL, F. Anthony LAI, and Stefan R. NAHORSKI. "Differential expression and regulation of ryanodine receptor and myo-inositol 1,4,5-trisphosphate receptor Ca2+ release channels in mammalian tissues and cell lines." Biochemical Journal 327, no. 1 (October 1, 1997): 251–58. http://dx.doi.org/10.1042/bj3270251.

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Ryanodine receptors (RyRs) and Ins(1,4,5)P3 receptors (Ins(1,4,5)P3Rs) represent two multigene families of channel proteins that mediate the release of Ca2+ ions from intracellular stores. In the present study, the expression patterns of these channel proteins in mammalian cell lines and tissues were investigated by using isoform-specific antibodies. All cell lines examined expressed two or more Ins(1,4,5)P3R isoforms, with the type 1 Ins(1,4,5)P3R being ubiquitous. RyR isoforms were detected in only six out of eight cell lines studied. Similarly, of the nine rabbit tissues examined, RyR protein expression was detected only in brain, heart, skeletal muscle and uterus. Specific [3H]ryanodine binding was found in a number of rabbit tissues, although it was not detected in mammalian cell lines. Subcellular fractionation of SH-SY5Y human neuroblastomas revealed that the type 2 RyR and type 1 Ins(1,4,5)P3R co-localize among the fractions of a sucrose-cushion separation of crude microsomal membrane fractions. Manipulation of SH-SY5Y cells by chronic stimulation of muscarinic acetylcholine receptor (mAChR) results in a decrease in their type 1 Ins(1,4,5)P3R levels but not in the abundance of the type 2 RyR. Differentiation of these neuroblastomas by using retinoic acid did not detectably alter their expression of Ca2+-release channel proteins. Finally, differentiation of BC3H1 cells affects the expression of their Ca2+-release channel proteins in an isoform-specific manner. In summary, this study demonstrates that mammalian cell lines display distinct patterns of Ca2+-release channel protein expression. The abundance of these proteins is differentially regulated during phenotypic modifications of a cell, such as differentiation or chronic stimulation of mAChR.

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VERMA, Vandana, Christine CARTER, Susan KEABLE, Deborah BENNETT, and Peter THORN. "Identification and function of type-2 and type-3 ryanodine receptors in gut epithelial cells." Biochemical Journal 319, no. 2 (October 15, 1996): 449–54. http://dx.doi.org/10.1042/bj3190449.

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Reverse transcription-PCR (RT-PCR) techniques were used to identify the expression of ryanodine receptor (RyR) isoforms in gut epithelial cells. Restriction digest and sequence analysis of the PCR product showed the presence of RyR 2 and RyR 3. [3H]Ry binding studies on a microsome preparation, in a high-salt buffer, showed specific binding with an EC50 of 15 µM. In order to determine a potential functional role for these RyRs, we first characterized the response of the cells to acetylcholine. At all concentrations used acetylcholine induced sinusoidal cytosolic Ca2+ concentration ([Ca2+]i) oscillations. In response to 10-4 M acetylcholine, levels of inositol 1,4,5-trisphosphate (InsP3) showed a peak of six times the basal level, at 30 s after stimulation. Application of caffeine alone failed to elicit a rise in cytosolic Ca2+. However, caffeine (5–50 mM) did rapidly and reversibly inhibit the acetylcholine-induced [Ca2+]i oscillations. The effects of Ry were more complex. Applied alone, Ry had no effect on the [Ca2+]i signal. When applied during agonist-evoked [Ca2+]i oscillations, Ry (10 µM) slowly blocked the response. In the continuous presence of Ry (10 µM) a short application of acetylcholine elicited a [Ca2+]i response that continued as oscillations even when the agonist was removed. The oscillations, in the presence of Ry (10 µM) but absence of agonist, were blocked either by removal of extracellular Ca2+ or by an application of a higher concentration of Ry (100 µM). These effects are consistent with the known use-dependence and dose-dependence for Ry action at the RyR. We conclude that the RyR 2 and RyR 3, identified by RT-PCR, play a central role in [Ca2+]i oscillations in gut epithelial cells.

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Brooksbank, Richard L., Margaret E. Badenhorts, Hyam Isaacs, and Nerina Savage. "Treatment of Normal Skeletal Muscle with FK506 or Rapamycin Results in Halothane-induced Muscle Contracture." Anesthesiology 89, no. 3 (September 1, 1998): 693–98. http://dx.doi.org/10.1097/00000542-199809000-00020.

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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.

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Moonga, Baljit S., Sun Li, Jameel Iqbal, Robert Davidson, Vijai S. Shankar, Peter J. R. Bevis, Angela Inzerillo, Etsuko Abe, Christopher L. H. Huang, and Mone Zaidi. "Ca2+ influx through the osteoclastic plasma membrane ryanodine receptor." American Journal of Physiology-Renal Physiology 282, no. 5 (May 1, 2002): F921—F932. http://dx.doi.org/10.1152/ajprenal.00045.2000.

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We predict that the type 2 ryanodine receptor isoform (RyR-2) located in the osteoclastic membrane functions as a Ca2+ influx channel and as a divalent cation (Ca2+) sensor. Cytosolic Ca2+ measurements revealed Ca2+ influx in osteoclasts at depolarized membrane potentials. The cytosolic Ca2+ change was, as expected, not seen in Ca2+-free medium and was blocked by the RyR modulator ryanodine. In contrast, at basal membrane potentials (∼25 mV) ryanodine triggered extracellular Ca2+ influx that was blocked by Ni2+. In parallel, single-channel recordings obtained from inside-out excised patches revealed a divalent cation-selective ∼60-pS conductance in symmetric solutions of Ba-aspartate [Ba-Asp; reversal potential ( E rev) ∼0 mV]. In the presence of a Ba2+ gradient, i.e., with Ba-Asp in the pipette and Na-Asp in the bath, channel conductance increased to ∼120 pS and E rev shifted to 21 mV. The conductance was tentatively classified as a RyR-gated Ca2+ channel as it displayed characteristic metastable states and was sensitive to ruthenium red and a specific anti-RyR antibody, Ab34. To demonstrate that extracellular Ca2+ sensing occurred at the osteoclastic surface rather than intracellularly, we performed protease protection assays using pronase. Preincubation with pronase resulted in markedly attenuated cytosolic Ca2+ signals triggered by either Ni2+(5 mM) or Cd2+ (50 μM). Finally, intracellular application of antiserum Ab34 potently inhibited divalent cation sensing. Together, these results strongly suggest the existence of 1) a membrane-resident Ca2+ influx channel sensitive to RyR modulators; 2) an extracellular, as opposed to intracellular, divalent cation activation site; and 3) a cytosolic CaM-binding regulatory site for RyR. It is likely therefore that the surface RyR-2 not only gates Ca2+ influx but also functions as a sensor for extracellular divalent cations.

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Conklin, Matthew W., Virginia Barone, Vincenzo Sorrentino, and Roberto Coronado. "Contribution of Ryanodine Receptor Type 3 to Ca2+ Sparks in Embryonic Mouse Skeletal Muscle." Biophysical Journal 77, no. 3 (September 1999): 1394–403. http://dx.doi.org/10.1016/s0006-3495(99)76988-2.

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Shao, Chun-Hong, Xander H. T. Wehrens, Todd A. Wyatt, Sheeva Parbhu, George J. Rozanski, Kaushik P. Patel, and Keshore R. Bidasee. "Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation." Journal of Applied Physiology 106, no. 4 (April 2009): 1280–92. http://dx.doi.org/10.1152/japplphysiol.91280.2008.

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The present study was undertaken to assess the effects of exercise training (ExT) initiated after the onset of diabetes on cardiac ryanodine receptor expression and function. Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin (STZ). Three weeks after STZ injection, diabetic rats were divided into two groups. One group underwent ExT for 4 wk while the other group remained sedentary. After 7 wk of sedentary diabetes, cardiac fractional shortening, rate of rise of left ventricular pressure, and myocyte contractile velocity were reduced by 14, 36, 44%, respectively. Spontaneous Ca2+ spark frequency increased threefold, and evoked Ca2+ release was dyssynchronous with diastolic Ca2+ releases. Steady-state type 2 ryanodine receptor (RyR2) protein did not change, but its response to Ca2+ was altered. RyR2 also exhibited 1.8- and 1.5-fold increases in phosphorylation at Ser2808 and Ser2814. PKA activity was reduced by 75%, but CaMKII activity was increased by 50%. Four weeks of ExT initiated 3 wk after the onset of diabetes blunted decreases in cardiac fractional shortening and rate of left ventricular pressure development, increased the responsiveness of the myocardium to isoproterenol stimulation, attenuated the increase in Ca2+ spark frequency, and minimized dyssynchronous and diastolic Ca2+ releases. ExT also normalized the responsiveness of RyR2 to Ca2+ activation, attenuated increases in RyR2 phosphorylation at Ser2808 and Ser2814, and normalized CaMKII and PKA activities. These data are the first to show that ExT during diabetes normalizes RyR2 function and Ca2+ release from the sarcoplasmic reticulum, providing insights into mechanisms by which ExT during diabetes improves cardiac function.

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Chiang, D. Y., N. Li, G. Wang, Q. Wang, A. Quick, D. Skapura, and X. H. T. Wehrens. "Impaired local regulation of ryanodine receptor type-2 by protein phosphatase 1 promotes atrial fibrillation." European Heart Journal 34, suppl 1 (August 2, 2013): P5016. http://dx.doi.org/10.1093/eurheartj/eht310.p5016.

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Chiang, David Y., Na Li, Qiongling Wang, Katherina M. Alsina, Ann P. Quick, Julia O. Reynolds, Guoliang Wang, et al. "Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation." Cardiovascular Research 103, no. 1 (May 8, 2014): 178–87. http://dx.doi.org/10.1093/cvr/cvu123.

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Clementi, Emilio, Maria Riccio, Clara Sciorati, Giuseppe Nisticò, and Jacopo Meldolesi. "The Type 2 Ryanodine Receptor of Neurosecretory PC12 Cells Is Activated by Cyclic ADP-ribose." Journal of Biological Chemistry 271, no. 30 (July 26, 1996): 17739–45. http://dx.doi.org/10.1074/jbc.271.30.17739.

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Zou, Yunzeng, Yanyan Liang, Hui Gong, Ning Zhou, Hong Ma, Aili Guan, Aijun Sun, et al. "Ryanodine Receptor Type 2 Is Required for the Development of Pressure Overload-Induced Cardiac Hypertrophy." Hypertension 58, no. 6 (December 2011): 1099–110. http://dx.doi.org/10.1161/hypertensionaha.111.173500.

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Dai, Shuiping, Duane D. Hall, and Johannes W. Hell. "Supramolecular Assemblies and Localized Regulation of Voltage-Gated Ion Channels." Physiological Reviews 89, no. 2 (April 2009): 411–52. http://dx.doi.org/10.1152/physrev.00029.2007.

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Abstract:

This review addresses the localized regulation of voltage-gated ion channels by phosphorylation. Comprehensive data on channel regulation by associated protein kinases, phosphatases, and related regulatory proteins are mainly available for voltage-gated Ca2+ channels, which form the main focus of this review. Other voltage-gated ion channels and especially Kv7.1-3 (KCNQ1-3), the large- and small-conductance Ca2+-activated K+ channels BK and SK2, and the inward-rectifying K+ channels Kir3 have also been studied to quite some extent and will be included. Regulation of the L-type Ca2+ channel Cav1.2 by PKA has been studied most thoroughly as it underlies the cardiac fight-or-flight response. A prototypical Cav1.2 signaling complex containing the β2 adrenergic receptor, the heterotrimeric G protein Gs, adenylyl cyclase, and PKA has been identified that supports highly localized via cAMP. The type 2 ryanodine receptor as well as AMPA- and NMDA-type glutamate receptors are in close proximity to Cav1.2 in cardiomyocytes and neurons, respectively, yet independently anchor PKA, CaMKII, and the serine/threonine phosphatases PP1, PP2A, and PP2B, as is discussed in detail. Descriptions of the structural and functional aspects of the interactions of PKA, PKC, CaMKII, Src, and various phosphatases with Cav1.2 will include comparisons with analogous interactions with other channels such as the ryanodine receptor or ionotropic glutamate receptors. Regulation of Na+ and K+ channel phosphorylation complexes will be discussed in separate papers. This review is thus intended for readers interested in ion channel regulation or in localization of kinases, phosphatases, and their upstream regulators.

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