scholarly journals Gating mechanism of cardiac ryanodine receptor 2 upon calcium ion binding

2020 ◽  
Author(s):  
Takuya Kobayashi ◽  
Akihisa Tsutsumi ◽  
Nagomi Kurebayashi ◽  
Kei Saito ◽  
Masami Kodama ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Heart Diseases ◽  
Atomic Level ◽  
Structural Basis ◽  
Ion Binding ◽  
Release Channel ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Channel Opening ◽  
Cardiac Ryanodine Receptor

AbstractCardiac ryanodine receptor (RyR2) is a large Ca2+ release channel in the sarcoplasmic reticulum and indispensable for excitation-contraction coupling in the heart. RyR2 is activated by Ca2+ and RyR2 mutations have been implicated in severe arrhythmogenic heart diseases. Yet, the structural basis underlying channel opening and how mutations affect the channel remain unknown. Here, we combined high-resolution structures determined by cryo-electron microscopy with quantitative functional analysis of channels carrying various mutations in specific residues. We demonstrated that interactions close to the channel pore are important for stabilizing the channel in the closed state and those in the surrounding regions are essential for channel opening. Our results reveal mechanisms underlying channel opening upon Ca2+ binding and alterations by pathogenic mutations of RyR2 at the atomic level.One Sentence SummaryKey movements and interactions in RyR2 during cardiac Ca2+ channel opening are clarified at the atomic level.

Antiarrhythmic Potential of Drugs Targeting the Cardiac Ryanodine Receptor Ca2+ Release Channel: Case Study of Dantrolene

2014 ◽  
Vol 21 (8) ◽  
pp. 1062-1072 ◽  
Author(s):  
Karoly Acsai ◽  
Norbert Nagy ◽  
Zoltan Marton ◽  
Kinga Oravecz ◽  
Andras Varro
Keyword(s):  
Ryanodine Receptor ◽  
Release Channel ◽  
Cardiac Ryanodine Receptor

Inactivation of the cardiac ryanodine receptor calcium release channel by nitric oxide

Cell Calcium ◽  
1997 ◽  
Vol 22 (6) ◽  
pp. 447-453 ◽  
Author(s):  
Alexandra Zahradníková ◽  
Igor Minarovic ◽  
Richard C. Venema ◽  
LászlóG. Meszaros
Keyword(s):  
Nitric Oxide ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Cardiac Ryanodine Receptor

Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2

Science ◽  
2016 ◽  
Vol 354 (6310) ◽  
pp. aah5324 ◽  
Author(s):  
Wei Peng ◽  
Huaizong Shen ◽  
Jianping Wu ◽  
Wenting Guo ◽  
Xiaojing Pan ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Structural Basis ◽  
Gating Mechanism

Redox regulation of the ryanodine receptor/calcium release channel

2006 ◽  
Vol 34 (5) ◽  
pp. 919-921 ◽  
Author(s):  
S. Zissimopoulos ◽  
F.A. Lai
Keyword(s):  
Ryanodine Receptor ◽  
Protein Interactions ◽  
Redox Regulation ◽  
Opposite Effect ◽  
Calcium Release ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Reducing Conditions ◽  
Channel Opening ◽  
Redox Sensitivity

The RyR (ryanodine receptor)/calcium release channel contains a number of highly reactive thiol groups that endow it with redox sensitivity. In general, oxidizing conditions favour channel opening, while reducing conditions have the opposite effect. Thiol modification affects the channel sensitivity to its principal effectors, Ca2+, Mg2+ and ATP, and alters RyR protein interactions. Here, we give a brief account of the major findings and prevailing views in the field.

scholarly journals Cryo-EM structure of the calcium homeostasis modulator 1 channel

2020 ◽  
Vol 6 (29) ◽  
pp. eaba8161
Author(s):  
Yue Ren ◽  
Tianlei Wen ◽  
Zhiqin Xi ◽  
Shunjin Li ◽  
Jing Lu ◽  
...  
Keyword(s):  
Calcium Homeostasis ◽  
Transmembrane Helix ◽  
Atp Release ◽  
Ion Permeation ◽  
Extracellular Loop ◽  
Release Channel ◽  
Dimer Interface ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Oligomeric Assembly

Calcium homeostasis modulator 1 (CALHM1) is a voltage-gated ATP release channel that plays an important role in neural gustatory signaling and the pathogenesis of Alzheimer’s disease. Here, we present a cryo–electron microscopy structure of full-length Ca2+-free CALHM1 from Danio rerio at an overall resolution of 3.1 Å. Our structure reveals an octameric architecture with a wide pore diameter of ~20 Å, presumably representing the active conformation. The overall structure is substantially different from that of the isoform CALHM2, which forms both undecameric hemichannels and gap junctions. The N-terminal small helix folds back to the pore and forms an antiparallel interaction with transmembrane helix 1. Structural analysis revealed that the extracellular loop 1 region within the dimer interface may contribute to oligomeric assembly. A positive potential belt inside the pore was identified that may modulate ion permeation. Our structure offers insights into the assembly and gating mechanism of the CALHM1 channel.

Cryo-EM structures of the human sodium-potassium pump revealing the gating mechanism on the cytoplasmic side

2021 ◽  
Author(s):  
Yingying Guo ◽  
Yuanyuan Zhang ◽  
Renhong Yan ◽  
Bangdong Huang ◽  
Fangfei Ye ◽  
...  
Keyword(s):  
Atp Hydrolysis ◽  
Structural Basis ◽  
Extracellular Potassium ◽  
Ion Pump ◽  
Sodium Potassium ◽  
Working Cycle ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Membrane Bound ◽  
Cytoplasmic Side

Abstract Na+/K+-ATPase (NKA) is a membrane-bound ion pump that generates electrochemical gradient of sodium ion and potassium ion across the plasma membrane via hydrolyzing ATP. During each so-called Post-Albers cycle, NKA exchanges three cytoplasmic sodium ions for two extracellular potassium ions through alternating E1 and E2 states. Hitherto, there are several steps remained unknown during the complete working cycle of NKA. Here, we report cryo-electron microscopy (cryo-EM) structures of recombinant over-expressed human NKA in three distinct states at 3.1–3.4 Å resolution, representing the E1·3Na state, in which the cytosolic gate is open, and the E1·3Na·ATP state preceding ATP hydrolysis and a basic E2·[2K] state. These structures reveal the ATP-dependent Na+-binding site remodeling for the close of the cytoplasmic gate, filling a gap in the structural elucidation of the Post-Albers cycle of NKA and providing structural basis for understanding the cytoplasmic Na+ entrance pathway.

scholarly journals Three-Dimensional Location of the Imperatoxin a Binding Site on the Ryanodine Receptor

1999 ◽  
Vol 146 (2) ◽  
pp. 493-500 ◽  
Author(s):  
Montserrat Samsó ◽  
Ramon Trujillo ◽  
Georgina B. Gurrola ◽  
Hector H. Valdivia ◽  
Terence Wagenknecht
Keyword(s):  
Binding Site ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Particle Image ◽  
Specific Binding ◽  
Three Dimensional ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Cryo Electron Microscopy ◽  
Peptide Toxin

Cryo-electron microscopy and three-dimensional, single-particle image analysis have been used to reveal the specific binding site of imperatoxin A (IpTxa) on the architecture of the calcium release channel/ryanodine receptor from skeletal muscle (RyR1). IpTxa is a peptide toxin that binds with high affinity to RyR1 and affects its functioning. The toxin was derivatized with biotin to enhance its detection with streptavidin. IpTxa binds to the cytoplasmic moiety of RyR1 between the clamp and handle domains, 11 nm away from the transmembrane pore. The proposed mimicry by IpTxa of the dihydropyridine receptor (DHPR) II-III loop, thought to be a main physiological excitation-contraction trigger, suggests that the IpTxa binding location is a potential excitation-contraction signal transduction site.

scholarly journals Investigations of the Contribution of a Putative Glycine Hinge to Ryanodine Receptor Channel Gating

2013 ◽  
Vol 288 (23) ◽  
pp. 16671-16679 ◽  
Author(s):  
Joanne Euden ◽  
Sammy A. Mason ◽  
Cedric Viero ◽  
N. Lowri Thomas ◽  
Alan J. Williams
Keyword(s):  
Ryanodine Receptor ◽  
Striated Muscle ◽  
Transmembrane Helix ◽  
Channel Gating ◽  
Disease Process ◽  
Structural Data ◽  
Structural Basis ◽  
Detailed Knowledge ◽  
Ion Translocation ◽  
Channel Opening

Ryanodine receptor channels (RyR) are key components of striated muscle excitation-contraction coupling, and alterations in their function underlie both inherited and acquired disease. A full understanding of the disease process will require a detailed knowledge of the mechanisms and structures involved in RyR function. Unfortunately, high-resolution structural data, such as exist for K+-selective channels, are not available for RyR. In the absence of these data, we have used modeling to identify similarities in the structural elements of K+ channel pore-forming regions and postulated equivalent regions of RyR. This has identified a sequence of residues in the cytosolic cavity-lining transmembrane helix of RyR (G4864LIIDA4869 in RyR2) analogous to the glycine hinge motif present in many K+ channels. Gating in these K+ channels can be disrupted by substitution of residues for the hinge glycine. We investigated the involvement of glycine 4864 in RyR2 gating by monitoring properties of recombinant human RyR2 channels in which this glycine is replaced by residues that alter gating in K+ channels. Our data demonstrate that introducing alanine at position 4864 produces no significant change in RyR2 function. In contrast, function is altered when glycine 4864 is replaced by either valine or proline, the former preventing channel opening and the latter modifying both ion translocation and gating. Our studies reveal novel information on the structural basis of RyR gating, identifying both similarities with, and differences from, K+ channels. Glycine 4864 is not absolutely required for channel gating, but some flexibility at this point in the cavity-lining transmembrane helix is necessary for normal RyR function.

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