The Ryanodine Receptor as a Sensor for Cellular Environments in Muscles

The ryanodine receptor (RyR) is a Ca2+ release channel in the sarcoplasmic reticulum of skeletal and cardiac muscles and plays a key role in excitation-contraction coupling. The activity of the RyR is regulated by many intracellular factors such as divalent cations (Ca2+ and Mg2+), nucleotides, associated proteins, and reactive oxygen species. Since these intracellular factors change depending on the condition of the muscle, e.g., exercise, fatigue, or disease states, the RyR channel activity will be altered accordingly. In this review, we describe how the RyR channel is regulated under various conditions and discuss the possibility that the RyR acts as a sensor for change in the cellular environment of muscles.

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The Ryanodine Receptor as a Sensor for Intracellular Environments in Muscles

International Journal of Molecular Sciences ◽

10.3390/ijms221910795 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10795

Author(s):

Takuya Kobayashi ◽

Nagomi Kurebayashi ◽

Takashi Murayama

Keyword(s):

Ryanodine Receptor ◽

Divalent Cations ◽

Oxygen Species ◽

Channel Activity ◽

Release Channel ◽

Contraction Coupling ◽

Disease States ◽

Associated Proteins ◽

Cardiac Muscles ◽

Exercise Fatigue

The ryanodine receptor (RyR) is a Ca2+ release channel in the sarcoplasmic reticulum of skeletal and cardiac muscles and plays a key role in excitation–contraction coupling. The activity of the RyR is regulated by the changes in the level of many intracellular factors, such as divalent cations (Ca2+ and Mg2+), nucleotides, associated proteins, and reactive oxygen species. Since these intracellular factors change depending on the condition of the muscle, e.g., exercise, fatigue, or disease states, the RyR channel activity will be altered accordingly. In this review, we describe how the RyR channel is regulated under various conditions and discuss the possibility that the RyR acts as a sensor for changes in the intracellular environments in muscles.

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Aldolase potentiates DIDS activation of the ryanodine receptor in rabbit skeletal sarcoplasmic reticulum

Biochemical Journal ◽

10.1042/bj20060701 ◽

2006 ◽

Vol 399 (2) ◽

pp. 325-333 ◽

Cited By ~ 4

Author(s):

In-Ra Seo ◽

Sang Hyun Moh ◽

Eun Hui Lee ◽

Gerhard Meissner ◽

Do Han Kim

Keyword(s):

Sarcoplasmic Reticulum ◽

Ryanodine Receptor ◽

Column Chromatography ◽

Anion Channel ◽

Affinity Column ◽

Open Probability ◽

Release Channel ◽

Affinity Column Chromatography ◽

Lifetime Analysis ◽

Associated Proteins

DIDS (4,4′-di-isothiocyanostilbene-2,2′-disulfonate), an anion channel blocker, triggers Ca2+ release from skeletal muscle SR (sarcoplasmic reticulum). The present study characterized the effects of DIDS on rabbit skeletal single Ca2+-release channel/RyR1 (ryanodine receptor type 1) incorporated into a planar lipid bilayer. When junctional SR vesicles were used for channel incorporation (native RyR1), DIDS increased the mean Po (open probability) of RyR1 without affecting unitary conductance when Cs+ was used as the charge carrier. Lifetime analysis of single RyR1 activities showed that 10 μM DIDS induced reversible long-lived open events (Po=0.451±0.038) in the presence of 10 μM Ca2+, due mainly to a new third component for both open and closed time constants. However, when purified RyR1 was examined in the same condition, 10 μM DIDS became considerably less potent (Po=0.206±0.025), although the caffeine response was similar between native and purified RyR1. Hence we postulated that a DIDS-binding protein, essential for the DIDS sensitivity of RyR1, was lost during RyR1 purification. DIDS-affinity column chromatography of solubilized junctional SR, and MALDI–TOF (matrix-assisted laser-desorption ionization–time-of-flight) MS analysis of the affinity-column-associated proteins, identified four major DIDS-binding proteins in the SR fraction. Among them, aldolase was the only protein that greatly potentiated DIDS sensitivity. The association between RyR1 and aldolase was further confirmed by co-immunoprecipitation and aldolase-affinity batch-column chromatography. Taken together, we conclude that aldolase is physically associated with RyR1 and could confer a considerable potentiation of the DIDS effect on RyR1.

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Propofol Potentiates Ca2+ Release Channel Activity of the Ryanodine Receptor in Rat Dorsal Root Ganglion Neurons

Anesthesiology ◽

10.1097/00000542-200209002-00708 ◽

2002 ◽

Vol 96 (Sup 2) ◽

pp. A708

Author(s):

Yasuyuki Homma ◽

Kristen Yankura ◽

Seok Kon Kim ◽

Manjunatha B. Bhat

Keyword(s):

Dorsal Root Ganglion ◽

Ryanodine Receptor ◽

Dorsal Root ◽

Dorsal Root Ganglion Neurons ◽

Channel Activity ◽

Release Channel ◽

Ganglion Neurons

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Modification of ryanodine receptor/Ca2+ release channel with dinitrofluorobenzene

Biochemical Journal ◽

10.1042/bj3420239 ◽

1999 ◽

Vol 342 (1) ◽

pp. 239-248 ◽

Cited By ~ 1

Author(s):

Nurit HADAD ◽

Wei FENG ◽

Varda SHOSHAN-BARMATZ

Keyword(s):

Ryanodine Receptor ◽

Single Channel ◽

Ruthenium Red ◽

Amino Group ◽

Channel Activity ◽

Closed Channel ◽

Release Channel ◽

Atp Binding Site ◽

Ph Values ◽

Stimulation Of

Modification of the ryanodine receptor (RyR)/Ca2+ release channel with 2,4-dinitrofluorobenzene (DNFB) indicated that two classes of amino group interact with the reagent, as can be distinguished on the basis of their reactivity/accessibility and the effects on ryanodine binding and single channel activities. One group interacted very rapidly (t½ < 30 s) at 25 °C with low concentrations of DNFB [C50 (concentration of DNFB required for 50% inhibition or stimulation of ryanodine binding) = 5 μM], and at pH values of 6.2 and higher. This interaction resulted in the marked stimulation of ryanodine binding and the complete inhibition of a single Ca2+ release channel incorporated into planar lipid bilayer. The second group is accessible at higher temperatures (37 °C); at pH values higher than 7.4 it reacted slowly (t½ = 20 min) with high concentrations of DNFB (C50 = 70 μM). This interaction led to the inhibition of ryanodine binding and single channel activity. Modification of RyR with DNFB under the stimulatory conditions resulted in 3.6-fold and 6-fold increases in ryanodine-binding and Ca2+-binding affinities respectively. Modification with DNFB under the inhibitory conditions resulted in a decrease in the total ryanodine-binding sites. The exposure of the RyR single channel to DNFB under both inhibitory and stimulatory conditions led to the complete closure of the channel. However, when modified under the stimulatory conditions, but not under the inhibitory ones, the DNFB-modified closed channel could be re-activated by sub-micromolar concentrations of ryanodine, in the presence of nanomolar concentrations of Ca2+. The DNFB-modified ryanodine-activated RyR channel showed fast transitions between open, closed and several sub-conductance states, and was completely closed by Ruthenium Red. ATP re-activated the DNFB-modified closed channel or, if present during modification, prevented the inhibition of RyR channel activity by DNFB. Neither the stimulation nor the inhibition of ryanodine binding by modification with DNFB was affected by the presence of ATP. By using the photoreactive ATP analogue 3′-O-(4-benzoyl)benzoyl-[α-32P]ATP we found that DNFB modification had no effect on the ATP-binding site of RyR. The results are discussed with regard to the involvement of amino group residues in channel gating, ryanodine association/dissociation and occlusion, and the relationship between the open/closed state of the RyR and its capacity to bind ryanodine.

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Expression of Ca2+-induced Ca2+ release channel activity from cardiac ryanodine receptor cDNA in Chinese hamster ovary cells

Journal of Molecular and Cellular Cardiology ◽

10.1016/0022-2828(92)90662-j ◽

1992 ◽

Vol 24 ◽

pp. 212

Author(s):

Toshiaki Imagawa ◽

Junichi Nakai ◽

Hiroshi Takeshima ◽

Shosaku Numa ◽

Munekazu Shigekawa

Keyword(s):

Ryanodine Receptor ◽

Chinese Hamster Ovary ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Channel Activity ◽

Release Channel ◽

Ovary Cells ◽

Receptor Cdna ◽

Cardiac Ryanodine Receptor

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

AJP Cell Physiology ◽

10.1152/ajpcell.2000.279.5.c1366 ◽

2000 ◽

Vol 279 (5) ◽

pp. C1366-C1374 ◽

Cited By ~ 21

Author(s):

Toshiharu Oba ◽

Tatsuya Ishikawa ◽

Takashi Murayama ◽

Yasuo Ogawa ◽

Mamoru Yamaguchi

Keyword(s):

Skeletal Muscle ◽

Lipid Bilayers ◽

Ryanodine Receptor ◽

Calcium Release ◽

Physiological Role ◽

Channel Activity ◽

Calcium Release Channel ◽

Open Probability ◽

Skeletal Muscle Function ◽

Release Channel

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

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