Regulation of the sarcoplasmic reticulum ryanodine receptor by inorganic phosphate.

Fruen, Bradley R.; Mickelson, James R.; Shomer, Nirah H.; Roghair, Timothy J.; Louis, Charles F.

doi:10.1016/s0021-9258(17)42333-7

Cited by 52 publications

(9 citation statements)

References 35 publications

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“…RyRs are complex macromolecules that open and close in response to a range of stimuli. Previously, it has been reported that the activity of RyRs can be influenced by anions (Fruen et al, 1994(Fruen et al, , 1996. For RyR2, tritiated ryanodine binding was found to be higher in 0.25M KCl versus 0.25M KMes (Liu et al, 1998), suggesting that chloride can increase the activity of RyR2.…”

Section: Structurementioning

confidence: 88%

The Cardiac Ryanodine Receptor N-Terminal Region Contains an Anion Binding Site that Is Targeted by Disease Mutations

et al. 2013

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Ryanodine receptors (RyRs) are calcium release channels located in the membrane of the endoplasmic and sarcoplasmic reticulum and play a major role in muscle excitation-contraction coupling. The cardiac isoform (RyR2) is the target for >150 mutations that cause catecholaminergic polymorphic ventricular tachycardia (CPVT) and other conditions. Here, we present the crystal structure of the N-terminal region of RyR2 (1-547), an area encompassing 29 distinct disease mutations. The protein folds up in three individual domains, which are held together via a central chloride anion that shields repulsive positive charges. Several disease mutant versions of the construct drastically destabilize the protein. The R420Q disease mutant causes CPVT and ablates chloride binding. The mutation results in reorientations of the first two domains relative to the third domain. These conformational changes likely activate the channel by destabilizing intersubunit interactions that are disrupted upon channel opening.

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Section: Structurementioning

confidence: 88%

The Cardiac Ryanodine Receptor N-Terminal Region Contains an Anion Binding Site that Is Targeted by Disease Mutations

et al. 2013

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“…We find the latter explanation more likely. Indeed, it is possible that the increased tetanic [Ca 2ϩ ] i following repeated contractions and heat exposure (8) is due to an elevated P i content, which will enhance ryanodine receptormediated Ca 2ϩ release (14). With respect to glycogen, under the conditions studied (heating), an enhancement of tetanic [Ca 2ϩ ] i cannot be explained by increases in glycogen.…”

Section: Discussionmentioning

confidence: 99%

“…The filter papers were dried, immersed into Ultima-Gold scintillation cocktail and counted for radioactivity. Glycogen synthase (GS) and glycogen phosphorylase were also assayed with filter paper techniques by determining the incorporation of label from UDP-[U- 14 C]glucose and ␣-D-[U-14 C]glucose-1-P into glycogen, respectively, essentially as described earlier (26). GS fractional activity represents the activity in the presence of 0.17/7.2 mM glucose 6-P (GSL/GSH, i.e., low-and high-glucose 6-P), and phosphorylase fractional activity represents the activity in the presence of 0/3.3 mM AMP (Phos a/Phos aϩb).…”

Section: Methodsmentioning

confidence: 99%

Heating after intense repeated contractions inhibits glycogen accumulation in mouse EDL muscle: role of phosphorylase in postexercise glycogen metabolism

Blackwood

Hanya

Katz

2018

American Journal of Physiology-Cell Physiology

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The effects of heating on glycogen synthesis (incorporation of [C]glucose into glycogen) and accumulation after intense repeated contractions were investigated. Isolated mouse extensor digitorum longus muscle (type II) was stimulated electrically to perform intense tetanic contractions at 25°C. After 120 min recovery at 25°C, glycogen accumulated to almost 80% of basal, whereas after recovery at 35°C, glycogen remained low (~25% of basal). Glycogen synthesis averaged 0.97±0.07 µmol/30 min/g wet wt during recovery at 25°C and 1.48±0.08 during recovery at 35°C (P<0.001). There were no differences in phosphorylase and glycogen synthase total activities, nor in phosphorylase fractional activity, whereas glycogen synthase fractional activity was increased by ~50% after recovery at 35°C vs. 25°C. Inorganic phosphate (Pi, substrate for phosphorylase) was markedly increased (~300% of basal) following contraction, but returned to control levels after 120 min recovery at 25°C. In contrast, Pi remained elevated after recovery at 35°C (>2-fold higher than recovery at 25°C). Estimates of glycogen breakdown indicated that phosphorylase activity (either via inhibition at 25°C or activation at 35°C) was responsible for ~60% of glycogen accumulation during recovery at 25°C and ~45% during recovery at 35°C. These data demonstrate that despite the enhancing effect of heating on glycogen synthesis during recovery from intense contractions, glycogen accumulation is inhibited owing to Pi-mediated activation of phosphorylase. Thus phosphorylase can play a quantitatively important role in glycogen biogenesis during recovery from repeated contractions in isolated type II muscle.

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“…A direct promotion of RyR opening would be consistent with earlier observations. Fruen et al (1994) reported a large increase in P open of bilayer-incorporated RyR1 in the presence of 3-30 mM P i on the cytosolic side. These authors speculated that the higher P open could explain the increased Ca 2+ release that occurs early in fatigue, possibly counteracting the decreased Ca 2+ sensitivity of the myofilaments.…”

Section: Cytosolic Effects Of P I On Spark Frequencymentioning

confidence: 96%

“…The Ca 2+ release process may be altered by high P i in various ways, including: (i) direct effects on the SR Ca 2+ release channel, (ii) inhibition of Ca 2+ uptake by the sarcoplasmic reticulum ATPase (SERCA), and (iii) reduction of the free Ca 2+ concentration in the SR, [Ca 2+ ] SR , upon precipitation of its salts. Fruen et al (1994) showed a potentiating effect of P i on RyRs incorporated in lipid bilayers, with an increase in open probability (P open ) of ß90% at 10 mM P i . Working with Xenopus laevis, Stienen et al (1999) reported a modest inhibition of Ca 2+ uptake by 30 mM P i , which increased when the pH was reduced to 6.2.…”

Section: Introductionmentioning

confidence: 95%

A chloride channel blocker prevents the suppression by inorganic phosphate of the cytosolic calcium signals that control muscle contraction

Ferreira

Pequera

Launikonis

et al. 2020

The Journal of Physiology

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Accumulation of inorganic phosphate (P i) may contribute to muscle fatigue by precipitating calcium salts inside the sarcoplasmic reticulum (SR). Neither direct demonstration of this process nor definition of the entry pathway of P i into SR are fully established. r We showed that P i promoted Ca 2+ release at concentrations below 10 mM and decreased it at higher concentrations. This decrease correlated well with that of [Ca 2+ ] SR. r Pre-treatment of permeabilized myofibres with 2 mM Cl − channel blocker 9-anthracenecarboxylic acid (9AC) inhibited both effects of P i. r The biphasic dependence of Ca 2+ release on [P i ] is explained by a direct effect of P i acting on the SR Ca 2+ release channel, combined with the intra-SR precipitation of Ca 2+ salts. The effects of 9AC demonstrate that P i enters the SR via a Cl − pathway of an as-yet-undefined molecular nature.

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Regulation of the sarcoplasmic reticulum ryanodine receptor by inorganic phosphate.

Cited by 52 publications

References 35 publications

The Cardiac Ryanodine Receptor N-Terminal Region Contains an Anion Binding Site that Is Targeted by Disease Mutations

The Cardiac Ryanodine Receptor N-Terminal Region Contains an Anion Binding Site that Is Targeted by Disease Mutations

Heating after intense repeated contractions inhibits glycogen accumulation in mouse EDL muscle: role of phosphorylase in postexercise glycogen metabolism

A chloride channel blocker prevents the suppression by inorganic phosphate of the cytosolic calcium signals that control muscle contraction

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