scholarly journals Direct binding of verapamil to the ryanodine receptor channel of sarcoplasmic reticulum

1990 ◽  
Vol 58 (2) ◽  
pp. 471-481 ◽  
Author(s):  
H.H. Valdivia ◽  
C. Valdivia ◽  
J. Ma ◽  
R. Coronado
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Direct Binding ◽  
Receptor Channel

scholarly journals Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators

2019 ◽  
Author(s):  
Ximin Chi ◽  
Deshun Gong ◽  
Kang Ren ◽  
Gewei Zhou ◽  
Gaoxingyu Huang ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Molecular Basis ◽  
Central Domain ◽  
Mechanistic Insight ◽  
Life Threatening ◽  
Cardiac Disorders ◽  
Insight Into ◽  
Receptor Channel

AbstractThe type-2 ryanodine receptor (RyR2) is responsible for releasing Ca2+ from the sarcoplasmic reticulum of cardiomyocytes, subsequently leading to muscle contraction. Here, we report four cryo-EM structures of porcine RyR2 bound to distinct modulators that collectively provide mechanistic insight into RyR2 regulation. Ca2+ alone induces a contraction of the Central domain that facilitates the dilation of S6 bundle, but is insufficient to open the pore. The small molecule agonist PCB95 helps Ca2+ to overcome the barrier for opening. FKBP12.6 induces a relaxation of the Central domain that decouples it from the S6 bundle, stabilizing RyR2 in a closed state. Caffeine locks the Central domain in a constitutively contracted state, while further addition of ATP opens the channel by strengthening the coupling between the U-motif and S6. Our study marks an important step towards mechanistic understanding of the complicated regulation of this key channel whose aberrant activity engenders life-threatening cardiac disorders.

scholarly journals Identification of the cardiac ryanodine receptor channel in membrane blebs of sarcoplasmic reticulum

FEBS Letters ◽  
2001 ◽  
Vol 505 (3) ◽  
pp. 419-425 ◽  
Author(s):  
Thomas Böhle ◽  
Mathias C. Brandt ◽  
Nadine Henn ◽  
Annette Schmidt ◽  
Wilhelm Bloch ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Membrane Blebs ◽  
Receptor Channel ◽  
Cardiac Ryanodine Receptor

Ryanodine Receptor Channel-Dependent Glutathione Transport in the Sarcoplasmic Reticulum of Skeletal Muscle

2001 ◽  
Vol 287 (3) ◽  
pp. 696-700 ◽  
Author(s):  
Miklós Csala ◽  
Rosella Fulceri ◽  
József Mandl ◽  
Angelo Benedetti ◽  
Gábor Bánhegyi
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Channel Dependent ◽  
Glutathione Transport ◽  
Receptor Channel

scholarly journals Peptide fragments of the dihydropyridine receptor can modulate cardiac ryanodine receptor channel activity and sarcoplasmic reticulum Ca2+ release

2004 ◽  
Vol 379 (1) ◽  
pp. 161-172 ◽  
Author(s):  
Angela F. DULHUNTY ◽  
Suzanne M. CURTIS ◽  
Louise CENGIA ◽  
Magdalena SAKOWSKA ◽  
Marco G. CASAROTTO
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Lipid Bilayers ◽  
Ryanodine Receptor ◽  
Helical Structure ◽  
Dihydropyridine Receptor ◽  
Dependent Manner ◽  
Channel Activity ◽  
Peptide Fragments ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Receptor Channel

We show that peptide fragments of the dihydropyridine receptor II–III loop alter cardiac RyR (ryanodine receptor) channel activity in a cytoplasmic Ca2+-dependent manner. The peptides were AC (Thr-793–Ala-812 of the cardiac dihydropyridine receptor), AS (Thr-671–Leu-690 of the skeletal dihydropyridine receptor), and a modified AS peptide [AS(D-R18)], with an extended helical structure. The peptides added to the cytoplasmic side of channels in lipid bilayers at ≥10 nM activated channels when the cytoplasmic [Ca2+] was 100 nM, but either inhibited or did not affect channel activity when the cytoplasmic [Ca2+] was 10 or 100 µM. Both activation and inhibition were independent of bilayer potential. Activation by AS, but not by AC or AS(D-R18), was reduced at peptide concentrations >1 µM in a voltage-dependent manner (at +40 mV). In control experiments, channels were not activated by the scrambled AS sequence (ASS) or skeletal II–III loop peptide (NB). Resting Ca2+ release from cardiac sarcoplasmic reticulum was not altered by peptide AC, but Ca2+-induced Ca2+ release was depressed. Resting and Ca2+-induced Ca2+ release were enhanced by both the native and modified AS peptides. NMR revealed (i) that the structure of peptide AS(D-R18) is not influenced by [Ca2+] and (ii) that peptide AC adopts a helical structure, particularly in the region containing positively charged residues. This is the first report of specific functional interactions between dihydropyridine receptor A region peptides and cardiac RyR ion channels in lipid bilayers.

scholarly journals A model for ionic conduction in the ryanodine receptor channel of sheep cardiac muscle sarcoplasmic reticulum.

1992 ◽  
Vol 100 (3) ◽  
pp. 495-517 ◽  
Author(s):  
A Tinker ◽  
A R Lindsay ◽  
A J Williams
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Binding Site ◽  
Ryanodine Receptor ◽  
Binding Sites ◽  
Ionic Conduction ◽  
Divalent Cations ◽  
Rate Theory ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Alkaline Earths ◽  
Receptor Channel

A model is developed for ionic conduction in the sheep cardiac sarcoplasmic reticulum ryanodine receptor channel based on Eyring rate theory. A simple scheme is proposed founded on single-ion occupancy and an energy profile with four barriers and three binding sites. The model is able to quantitatively predict a large number of conduction properties of the purified and native receptor with monovalent and divalent cations as permeant species. It suggests that discrimination between divalent and monovalent cations is due to a high affinity central binding site and a process that favors the passage of divalent cations between binding sites. Furthermore, differences in conductance among the group Ia cations and among the alkaline earths are largely explained by differing affinity at this putative central binding site.

scholarly journals Measurement of RyR permeability reveals a role of calsequestrin in termination of SR Ca2+ release in skeletal muscle

2011 ◽  
Vol 138 (2) ◽  
pp. 231-247 ◽  
Author(s):  
Monika Sztretye ◽  
Jianxun Yi ◽  
Lourdes Figueroa ◽  
Jingsong Zhou ◽  
Leandro Royer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Sarcoplasmic Reticulum ◽  
Voltage Clamp ◽  
Ryanodine Receptor ◽  
Release Flux ◽  
Consequent Reduction ◽  
First Time ◽  
Receptor Channel

The mechanisms that terminate Ca2+ release from the sarcoplasmic reticulum are not fully understood. D4cpv-Casq1 (Sztretye et al. 2011. J. Gen. Physiol. doi:10.1085/jgp.201010591) was used in mouse skeletal muscle cells under voltage clamp to measure free Ca2+ concentration inside the sarcoplasmic reticulum (SR), [Ca2+]SR, simultaneously with that in the cytosol, [Ca2+]c, during the response to long-lasting depolarization of the plasma membrane. The ratio of Ca2+ release flux (derived from [Ca2+]c(t)) over the gradient that drives it (essentially equal to [Ca2+]SR) provided directly, for the first time, a dynamic measure of the permeability to Ca2+ of the releasing SR membrane. During maximal depolarization, flux rapidly rises to a peak and then decays. Before 0.5 s, [Ca2+]SR stabilized at ∼35% of its resting level; depletion was therefore incomplete. By 0.4 s of depolarization, the measured permeability decayed to ∼10% of maximum, indicating ryanodine receptor channel closure. Inactivation of the t tubule voltage sensor was immeasurably small by this time and thus not a significant factor in channel closure. In cells of mice null for Casq1, permeability did not decrease in the same way, indicating that calsequestrin (Casq) is essential in the mechanism of channel closure and termination of Ca2+ release. The absence of this mechanism explains why the total amount of calcium releasable by depolarization is not greatly reduced in Casq-null muscle (Royer et al. 2010. J. Gen. Physiol. doi:10.1085/jgp.201010454). When the fast buffer BAPTA was introduced in the cytosol, release flux became more intense, and the SR emptied earlier. The consequent reduction in permeability accelerated as well, reaching comparable decay at earlier times but comparable levels of depletion. This observation indicates that [Ca2+]SR, sensed by Casq and transmitted to the channels presumably via connecting proteins, is determinant to cause the closure that terminates Ca2+ release.

scholarly journals The Interaction of a Neutral Ryanoid with the Ryanodine Receptor Channel Provides Insights into the Mechanisms by Which Ryanoid Binding Is Modulated by Voltage

2000 ◽  
Vol 116 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Bhavna Tanna ◽  
William Welch ◽  
Luc Ruest ◽  
John L. Sutko ◽  
Alan J. Williams
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Transmembrane Potential ◽  
Voltage Dependence ◽  
Voltage Drop ◽  
Release Channel ◽  
Receptor Affinity ◽  
A Site ◽  
Positively Charged ◽  
Receptor Channel

In an earlier investigation, we demonstrated that the likelihood of interaction of a positively charged ryanoid, 21-amino-9α-hydroxyryanodine, with the sarcoplasmic reticulum Ca2+-release channel (ryanodine receptor, RyR) is dependent on holding potential (Tanna, B., W. Welch, L. Ruest, J.L. Sutko, and A.J. Williams. 1998. J. Gen. Physiol. 112:55–69) and suggested that voltage dependence could result from either the translocation of the charged ligand to a site within the voltage drop across the channel or a voltage-driven alteration in receptor affinity. We now report experiments that allow us to assess the validity of these alternate mechanisms. Ryanodol is a neutral ryanoid that binds to RyR and induces modification of channel function. By determining the influence of transmembrane potential on the probability of channel modification by ryanodol and the rate constants of ryanodol association and dissociation, we demonstrate that the influence of voltage is qualitatively the same for both the neutral and positively charged ryanoids. These experiments establish that most, if not all, of the modification of ryanoid interaction with RyR by transmembrane holding potential results from a voltage-driven alteration in receptor affinity.

Ryanodine receptor channel of sarcoplasmic reticulum

1988 ◽  
Vol 11 (10) ◽  
pp. 453-457 ◽  
Author(s):  
Michael Fill ◽  
Roberto Coronado
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Receptor Channel
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