Ryanodine

Aging Effects of Caenorhabditis elegans Ryanodine Receptor Variants Corresponding to Human Myopathic Mutations.[Pubmed:28325813]

G3 (Bethesda). 2017 May 5;7(5):1451-1461.

Delaying the decline in skeletal muscle function will be critical to better maintenance of an active lifestyle in old age. The skeletal muscle Ryanodine receptor, the major intracellular membrane channel through which calcium ions pass to elicit muscle contraction, is central to calcium ion balance and is hypothesized to be a significant factor for age-related decline in muscle function. The nematode Caenorhabditis elegans is a key model system for the study of human aging, and strains were generated with modified C. elegans Ryanodine receptors corresponding to human myopathic variants linked with malignant hyperthermia and related conditions. The altered response of these strains to pharmacological agents reflected results of human diagnostic tests for individuals with these pathogenic variants. Involvement of nerve cells in the C. elegans responses may relate to rare medical symptoms concerning the central nervous system that have been associated with Ryanodine receptor variants. These single amino acid modifications in C. elegans also conferred a reduction in lifespan and an accelerated decline in muscle integrity with age, supporting the significance of Ryanodine receptor function for human aging.

Basal ryanodine receptor activity suppresses autophagic flux.[Pubmed:28322744]

Biochem Pharmacol. 2017 May 15;132:133-142.

The inositol 1,4,5-trisphosphate receptors (IP3Rs) and intracellular Ca(2+) signaling are critically involved in regulating different steps of autophagy, a lysosomal degradation pathway. The Ryanodine receptors (RyR), intracellular Ca(2+)-release channels mainly expressed in excitable cell types including muscle and neurons, have however not yet been extensively studied in relation to autophagy. Yet, aberrant expression and excessive activity of RyRs in these tissues has been implicated in the onset of several diseases including Alzheimer's disease, where impaired autophagy regulation contributes to the pathology. In this study, we determined whether pharmacological RyR inhibition could modulate autophagic flux in ectopic RyR-expressing models, like HEK293 cells and in cell types that endogenously express RyRs, like C2C12 myoblasts and primary hippocampal neurons. Importantly, RyR3 overexpression in HEK293 cells impaired the autophagic flux. Conversely, in all cell models tested, pharmacological inhibition of endogenous or ectopically expressed RyRs, using dantrolene or Ryanodine, augmented autophagic flux by increasing lysosomal turn-over (number of autophagosomes and autolysosomes measured as mCherry-LC3 punctae/cell increased from 70.37+/-7.81 in control HEK RyR3 cells to 111.18+/-7.72 and 98.14+/-7.31 after dantrolene and Ryanodine treatments, respectively). Moreover, in differentiated C2C12 cells, transmission electron microscopy demonstrated that dantrolene treatment decreased the number of early autophagic vacuoles from 5.9+/-2.97 to 1.8+/-1.03 per cellular cross section. The modulation of the autophagic flux could be linked to the functional inhibition of RyR channels as both RyR inhibitors efficiently diminished the number of cells showing spontaneous RyR3 activity in the HEK293 cell model (from 41.14%+/-2.12 in control cells to 18.70%+/-2.25 and 9.74%+/-2.67 after dantrolene and Ryanodine treatments, respectively). In conclusion, basal RyR-mediated Ca(2+)-release events suppress autophagic flux at the level of the lysosomes.

Arrhythmic effects of Epac-mediated ryanodine receptor activation in Langendorff-perfused murine hearts are associated with reduced conduction velocity.[Pubmed:28316073]

Clin Exp Pharmacol Physiol. 2017 Jun;44(6):686-692.

Recent papers have attributed arrhythmic substrate in murine RyR2-P2328S hearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct exchange protein directly activated by cAMP (Epac)-mediated Ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential (MAP) recordings demonstrated that initial steady (8 Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff-perfused wild-type mouse ventricles before pharmacological intervention. The Epac activator 8-CPT (8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate) (VT in 1 of 7 hearts), and the RyR2 blocker dantrolene, either alone (0 of 11) or with 8-CPT (0 of 9) did not then increase VT incidence (P>.05). Both progressively increased pacing rates and programmed extrasystolic (S2) stimuli similarly produced no VT in untreated hearts (n=20 and n=9 respectively). 8-CPT challenge then increased VT incidences (5 of 7 and 4 of 8 hearts respectively; P<.05). However, dantrolene, whether alone (0 of 10 and 1 of 13) or combined with 8-CPT (0 of 10 and 0 of 13) did not increase VT incidence relative to those observed in untreated hearts (P>.05). 8-CPT but not dantrolene, whether alone or combined with 8-CPT, correspondingly increased AP latencies (1.14+/-0.04 (n=7), 1.04+/-0.03 (n=10), 1.09+/-0.05 (n=8) relative to respective control values). In contrast, AP durations, conditions for 2:1 conduction block and ventricular effective refractory periods remained unchanged throughout. We thus demonstrate for the first time that acute RyR2 activation reversibly induces VT in specific association with reduced CV.

Respiratory muscle contractile inactivity induced by mechanical ventilation in piglets leads to leaky ryanodine receptors and diaphragm weakness.[Pubmed:28260211]

J Muscle Res Cell Motil. 2017 Feb;38(1):17-24.

Respiratory muscle contractile inactivity during mechanical ventilation (MV) induces diaphragm muscle weakness, a condition referred to as ventilator-induced diaphragmatic dysfunction (VIDD). Although VIDD pathophysiological mechanisms are still not fully understood, it has been recently suggested that remodeling of the sarcoplasmic reticulum (SR) calcium release channel/Ryanodine receptors (RyR1) in the diaphragm is a proximal mechanism of VIDD. Here, we used piglets, a large animal model of VIDD that is more relevant to human pathophysiology, to determine whether RyR1 alterations are observed in the presence of diaphragm weakness. In piglets, diaphragm weakness induced by 72 h of respiratory muscle unloading was associated with SR RyR1 remodeling and abnormal resting SR Ca(2+) leak in the diaphragm. Specifically, following controlled mechanical ventilation, diaphragm contractile function was reduced. Moreover, RyR1 macromolecular complexes were more oxidized, S-nitrosylated and phosphorylated at Ser-2844 and depleted of the stabilizing subunit calstabin1 compared with controls on adaptive support ventilation that maintains diaphragmatic contractile activity. Our study strongly supports the hypothesis that RyR1 is a potential therapeutic target in VIDD and the interest of using small molecule drugs to prevent RyR1-mediated SR Ca(2+) leak induced by respiratory muscle unloading in patients who require controlled mechanical ventilation.

Conformation state of the ryanodine receptor and functional effects of ryanodine on skeletal muscle.[Pubmed:9174102]

Biochem Pharmacol. 1997 Apr 4;53(7):909-12.

The Ryanodine receptor (RyR) and the dihydropyridine (DHP) receptor (L-channels) comprise the main elements of the functional feet of the triadic element in skeletal muscle. These two main elements have conformational states that are regulated by the membrane potential and the consequent electrical field. The pharmacological action of Ryanodine on skeletal muscle depends upon the physiological functional state of the RyR. At a resting potential of -90 m V, Ryanodine at very low concentrations, 10(-11) M, causes the RyR to have a low conductance state which allows calcium to leak from the terminal cisternae of the sarcoplasmic reticulum and to be recycled with ATP utilization, leading to a marked increase in oxygen consumption and aerobic metabolism. At concentrations greater than 10(-6) M, Ryanodine can cause a slowly developing contracture of resting muscle, inhibit the muscle twitch when the RyR complex is formed during stimulation, and, if formed before stimulation, accelerate the development of contracture. Biochemical studies have revealed that the RyR has four binding sites in which the conductance state depends upon the number of sites occupied by Ryanodine. Our present understanding of the RyR-operated calcium channel is the result of an interdisciplinary approach in which each discipline (anatomy, physiology, biophysics, and biochemistry) contributes to our knowledge of the pharmacological action of Ryanodine.

The pharmacology of ryanodine and related compounds.[Pubmed:9085309]

Pharmacol Rev. 1997 Mar;49(1):53-98.

The goal of this review has been to describe the current state of the pharmacology of Ryanodine and related compounds relative to the vertebrate RyRs. Resolution of questions concerning the molecular properties of RyR channel function and the contributions made by the RyR isoforms to cellular signaling in a variety of tissues will require the production of new pharmacological agents directed against these proteins. Novel naturally occurring Ryanodine congeners have been identified, and significant advances have been made in developing chemical approaches that permit the structure of Ryanodine to be derivatized in selective ways. Moreover, several of these changes have yielded compounds that differ in their binding affinities and in their abilities to modify the properties of the RyR channels. These advances give substance to the possibility of designing the required pharmacological agents based on rational design changes of the structure Ryanodine.

Ryanodine: a modifier of sarcoplasmic reticulum calcium release in striated muscle.[Pubmed:2415406]

Fed Proc. 1985 Dec;44(15):2984-8.

We have proposed that the naturally occurring alkaloid Ryanodine reduces the release of calcium from the sarcoplasmic reticulum (SR) in cardiac muscle cells. We summarize the data that support this hypothesis and discuss possible mechanisms for 1) the differences in sensitivity to Ryanodine displayed by intact skeletal and cardiac muscle preparations vs. that of skinned cardiac cells and isolated SR membranes, 2) the ability of Ryanodine to cause either an increase or a decrease in calcium accumulation by isolated skeletal muscle SR vesicles depending on experimental conditions, and 3) the positive inotropic effects produced by Ryanodine in cardiac muscle preparations under certain experimental circumstances. In addition, we also show how Ryanodine can be used to evaluate the contributions made by SR calcium release to cellular events in striated muscle.

Ryanodine is a cell permeant ryanodine receptor modulator. Ryanodine can either stimulate or inhibit Ryanodine-mediated Ca2+ release depending on its concentrations. Poisonous diterpenoid found in Ryania speciosa.

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