Ryanodine receptors (RyRs) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons.[1]
There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.
Contents
1Etymology
2Isoforms
3Physiology
4Associated proteins
5Pharmacology
5.1Ryanodine
5.2Caffeine
6Role in disease
7Structure
8See also
9References
10External links
Etymology
Ryanodine
The ryanodine receptors are named after the plant alkaloid ryanodine which shows a high affinity to them.
Isoforms
There are multiple isoforms of ryanodine receptors:
RyR1 is primarily expressed in skeletal muscle
RyR2 is primarily expressed in myocardium (heart muscle)
RyR3 is expressed more widely, but especially in the brain.[2]
Non-mammalian vertebrates typically express two RyR isoforms, referred to as RyR-alpha and RyR-beta.
Many invertebrates, including the model organisms Drosophila melanogaster (fruitfly) and Caenorhabditis elegans, only have a single isoform. In non-metazoan species, calcium-release channels with sequence homology to RyRs can be found, but they are shorter than the mammalian ones and may be closer to IP3 Receptors.
ryanodine receptor 1 (skeletal)
Identifiers
Symbol
RYR1
Alt. symbols
MHS, MHS1, CCO
NCBI gene
6261
HGNC
10483
OMIM
180901
RefSeq
NM_000540
UniProt
P21817
Other data
Locus
Chr. 19 q13.1
ryanodine receptor 2 (cardiac)
Identifiers
Symbol
RYR2
NCBI gene
6262
HGNC
10484
OMIM
180902
RefSeq
NM_001035
UniProt
Q92736
Other data
Locus
Chr. 1 q42.1-q43
ryanodine receptor 3
Identifiers
Symbol
RYR3
NCBI gene
6263
HGNC
10485
OMIM
180903
RefSeq
NM_001036
UniProt
Q15413
Other data
Locus
Chr. 15 q14-q15
Physiology
Ryanodine receptors mediate the release of calcium ions from the sarcoplasmic reticulum and endoplasmic reticulum, an essential step in muscle contraction.[1] In skeletal muscle, activation of ryanodine receptors occurs via a physical coupling to the dihydropyridine receptor (a voltage-dependent, L-type calcium channel), whereas, in cardiac muscle, the primary mechanism of activation is calcium-induced calcium release, which causes calcium outflow from the sarcoplasmic reticulum.[3]
It has been shown that calcium release from a number of ryanodine receptors in a ryanodine receptor cluster results in a spatiotemporally restricted rise in cytosolic calcium that can be visualised as a calcium spark.[4] Ryanodine receptors are very close to mitochondria and calcium release from RyR has been shown to regulate ATP production in heart and pancreas cells.[5][6][7]
Ryanodine receptors are similar to the inositol trisphosphate (IP3) receptor, and stimulated to transport Ca2+ into the cytosol by recognizing Ca2+ on its cytosolic side, thus establishing a positive feedback mechanism; a small amount of Ca2+ in the cytosol near the receptor will cause it to release even more Ca2+ (calcium-induced calcium release/CICR).[1] However, as the concentration of intracellular Ca2+ rises, this can trigger closing of RyR, preventing the total depletion of SR. This finding therefore indicates that a plot of opening probability for RyR as a function of Ca2+ concentration is a bell-curve.[8] Furthermore, RyR can sense the Ca2+ concentration inside the ER/SR and spontaneously open in a process known as store overload-induced calcium release (SOICR).[9]
RyRs are especially important in neurons and muscle cells. In heart and pancreas cells, another second messenger (cyclic ADP-ribose) takes part in the receptor activation.
The localized and time-limited activity of Ca2+ in the cytosol is also called a Ca2+ wave. The building of the wave is done by
the feedback mechanism of the ryanodine receptor
the activation of phospholipase C by GPCR or RTK, which leads to the production of inositol trisphosphate, which in turn activates the InsP3 receptor.
Associated proteins
RyRs form docking platforms for a multitude of proteins and small molecule ligands.[1]
The cardiac-specific isoform of the receptor (RyR2) is known to form a quaternary complex with luminal calsequestrin, junctin, and triadin.[10] Calsequestrin has multiple Ca2+ binding sites and binds Ca2+ ions with very low affinity so they can be easily released.
Pharmacology
Antagonists:[11]
Ryanodine locks the RyRs at half-open state at nanomolar concentrations, yet fully closes them at micromolar concentration.
Dantrolene the clinically used antagonist
Ruthenium red
procaine, tetracaine, etc. (local anesthetics)
Activators:[12]
Agonist: 4-chloro-m-cresol and suramin are direct agonists, i.e., direct activators.
Xanthines like caffeine and pentifylline activate it by potentiating sensitivity to native ligand Ca.
Physiological agonist: Cyclic ADP-ribose can act as a physiological gating agent. It has been suggested that it may act by making FKBP12.6 (12.6 kilodalton FK506 binding protein, as opposed to 12 kDa FKBP12 which binds to RyR1) which normally bind (and blocks) RyR2 channel tetramer in an average stoichiometry of 3.6, to fall off RyR2 (which is the predominant RyR in pancreatic beta cells, cardiomyocytes and smooth muscles).[13]
A variety of other molecules may interact with and regulate ryanodine receptor. For example: dimerized Homer physical tether linking inositol trisphosphate receptors (IP3R) and ryanodine receptors on the intracellular calcium stores with cell surface group 1 metabotropic glutamate receptors and the Alpha-1D adrenergic receptor[14]
Ryanodine
The plant alkaloid ryanodine, for which this receptor was named, has become an invaluable investigative tool. It can block the phasic release of calcium, but at low doses may not block the tonic cumulative calcium release. The binding of ryanodine to RyRs is use-dependent, that is the channels have to be in the activated state. At low (<10 micromolar, works even at nanomolar) concentrations, ryanodine binding locks the RyRs into a long-lived subconductance (half-open) state and eventually depletes the store, while higher (~100 micromolar) concentrations irreversibly inhibit channel-opening.
Caffeine
RyRs are activated by millimolar caffeine concentrations. High (greater than 5 mmol/L) caffeine concentrations cause a pronounced increase (from micromolar to picomolar) in the sensitivity of RyRs to Ca2+ in the presence of caffeine, such that basal Ca2+ concentrations become activatory. At low millimolar caffeine concentrations, the receptor opens in a quantal way, but has complicated behavior in terms of repeated use of caffeine or dependence on cytosolic or luminal calcium concentrations.
Role in disease
RyR1 mutations are associated with malignant hyperthermia and central core disease. RyR2 mutations play a role in stress-induced polymorphic ventricular tachycardia (a form of cardiac arrhythmia) and ARVD.[2] It has also been shown that levels of type RyR3 are greatly increased in PC12 cells overexpressing mutant human Presenilin 1, and in brain tissue in knockin mice that express mutant Presenilin 1 at normal levels,[citation needed] and thus may play a role in the pathogenesis of neurodegenerative diseases, like Alzheimer's disease.[citation needed]
The presence of antibodies against ryanodine receptors in blood serum has also been associated with myasthenia gravis.[1]
Structure
RyR1 cryo-EM structure revealed a large cytosolic assembly built on an extended α-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture shares the general structure of the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by Ca2+.[1][15]
See also
Ryanoid, a class of insecticide that act through ryanodine receptors
References
^ abcdefSantulli, Gaetano; Marks, Andrew (2015). "Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging". Current Molecular Pharmacology. 8 (2): 206–222. doi:10.2174/1874467208666150507105105. ISSN 1874-4672.
^ abZucchi R, Ronca-Testoni S (March 1997). "The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states". Pharmacol. Rev. 49 (1): 1–51. PMID 9085308.
^Fabiato A (1983). "Calcium-induced calcium release of calcium from the cardiac sarcoplasmic reticulum". Am J Physiol. 245 (1): C1–C14. doi:10.1152/ajpcell.1983.245.1.C1. PMID 6346892.
^Vites AM, Pappano AJ (1994). "Distinct modes of inhibition by ruthenium red and ryanodine of calcium-induced calcium release in avian atrium". J Pharmacol Exp Ther. 268 (3): 1476–84. PMID 7511166.
^Xu L, Tripathy A, Pasek DA, Meissner G (1998). "Potential for pharmacology of ryanodine receptor/calcium release channels". Ann N Y Acad Sci. 853: 130–48. doi:10.1111/j.1749-6632.1998.tb08262.x. PMID 10603942.
^Wang YX, Zheng YM, Mei QB, Wang QS, Collier ML, Fleischer S, Xin HB, Kotlikoff MI (2004). "FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells". Am J Physiol Cell Physiol. 286 (3): C538–46. doi:10.1152/ajpcell.00106.2003. PMID 14592808.
^Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ, Worley PF (1998). "Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors". Neuron. 21 (4): 717–26. doi:10.1016/S0896-6273(00)80589-9. PMID 9808459.
^Zalk R, Clarke OB, des Georges A, Grassucci RA, Reiken S, Mancia F, Hendrickson WA, Frank J, Marks AR (1 December 2014). "Structure of a mammalian ryanodine receptor". Nature. 517: 44–9. doi:10.1038/nature13950. PMC 4300236. PMID 25470061.
External links
Ryanodine+Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
v
t
e
Membrane transport protein: ion channels (TC 1A)
Ca2+: Calcium channel
Ligand-gated
Inositol trisphosphate receptor
1
2
3
Ryanodine receptor
1
2
3
Voltage-gated
L-type/Cavα
1.1
1.2
1.3
1.4
N-type/Cavα2.2
P-type/Cavα
2.1
Q-type/Cavα2.1
R-type/Cavα2.3
T-type/Cavα
3.1
3.2
3.3
α2δ-subunits
1
2
β-subunits
β1
β2
β3
β4
γ-subunits
γ1
γ2
γ3
γ4
Cation channels of sperm
1
2
3
4
Two-pore channel
1
2
Na+: Sodium channel
Constitutively active
Epithelial sodium channel
α
β
γ
δ
Proton-gated
Amiloride-sensitive cation channel
1
2
3
4
Voltage-gated
Navα
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
7A
Navβ
1
2
3
4
K+: Potassium channel
Calcium-activated
BK channel
α1
β1
β2
β3
β4
SK channel
SK1
SK2
SK3
IK channel
IK1
KCa
1.1
2.1
2.2
2.3
3.1
4.1
4.2
5.1
Inward-rectifier
KATP
Kir
1.1
2.1
2.2
2.3
2.4
2.6
GIRK/Kir
3.1
3.2
3.3
3.4
Kir
4.1
4.2
5.1
6.1
6.2
7.1
Tandem pore domain
K2P
1
2
3
4
5
6
7
9
10
12
13
15
16
17
18
Voltage-gated
Kvα1-6
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
2.1
2.2
3.1
3.2
3.3
3.4
4.1
4.2
4.3
5.1
6.1
6.2
6.3
6.4
Kvα7-12
7.1
7.2
7.3
7.4
7.5
8.1
8.2
9.1
9.2
9.3
10.1
10.2
11.1/hERG
11.2
11.3
12.1
12.2
12.3
Kvβ
1
2
3
KCNIP
1
2
3
4
minK/ISK
minK/ISK-like
MiRP
1
2
3
Shaker (gene)
Miscellaneous
Cl−: Chloride channel
Calcium-activated chloride channels
Anoctamin
ANO1
Bestrophin
1
2
Chloride Channel Accessory
1
2
3
4
CFTR
CLCN
1
2
3
4
5
6
7
KA
KB
CLIC
1
2
3
4
5
6
L1
CLNS
1A
1B
H+: Proton channel
HVCN1
M+: CNG cation channel
α
1
2
3
4
β
1
2
3
HCN
FC
1
2
3
4
M+: TRP cation channel
TRPA (1)
TRPC
1
2
3
4
4AP
5
6
7
TRPM
1
2
3
4
5
6
7
8
TRPML
1
2
3
TRPN
TRPP
1
2
TRPV
1
2
3
4
5
6
H2O (+ solutes): Porin
Aquaporin
0
1
2
3
4
5
6
7
8
9
Voltage-dependent anion channel
1
2
3
General bacterial porin family
Cytoplasm: Gap junction
Connexin
A
GJA1
GJA3
GJA4
GJA5
GJA8
GJA9
GJA10
B
GJB1
GJB2
GJB3
GJB4
GJB5
GJB6
GJB7
C
GJC1
GJC2
GJC3
D
GJD2
GJD3
GJD4
Innexin
By gating mechanism
Ion channel class
Ligand-gated
Light-gated
Voltage-gated
Stretch-activated
see also disorders
v
t
e
Cell signaling: calcium signaling and calcium metabolism
Cell membrane
Adhesion molecules
Cadherins
CDH1
CDH2
CDH3
CDH4
CDH5
CDH4
CDH5
CDH6
CDH7
CDH8
CDH9
CDH10
CDH11
CDH12
CDH13
CDH14
CDH15
CDH16
CDH17
Calcium channels
Ligand-gated
5-HT3 receptor
Ionotropic glutamate receptors
AMPA receptors
Kainate receptors
NMDA receptors
P2X receptors
Voltage-gated
L
N
P
R
T
TRP channels
TRPA
TRPC
TRPV
Calcium pumps
Sodium-calcium exchangers
SLC3A2
SLC8A1
GPCRs
Calcium-sensing receptor
Annexins
A1
A2
A3
A4
A5
A6
A7
A8
A8-L2
A9
A10
A11
A12
A13
Intracellular signaling
Second messengers
IP3
NAADP
cADPR
Intracellular channels
IP3 receptor
Ryanodine receptor
Calcium-induced calcium release
Intracellular pumps
SERCA
ATP2A1
ATP2A2
ATP2A3
Sodium-calcium exchangers
SLC8B1
SLC24A5
Sensors and chelators
Calbindin
Calmodulin
CALM1
CALM2
CALM3
CALML3
CALML5
Calsequestrin
Calretinin
Gelsolin
Neuronal calcium sensors
Calsenilin
Frequenin
GUCA
1A
1B
Hippocalcin
Neurocalcin
Recoverin
Visinin
Pervalbumin
Phospholamban
Sarcalumenin
Synaptotagmins
SYT1
SYT2
SYT3
SYT4
SYT5
SYT6
SYT7
SYT9
SYT11
SYT13
SYT14
S100
S100P
Troponin C
TNNC1
TNNC2
Calcium-dependent chaperones
Calreticulin
Calnexin
HSPA5
HSP90B1
Calcium-dependent kinases
CaM kinases
CAMK1
CAMK2
A
B
D
G
CAMK3
CAMK4
Protein kinase C
Calcium-dependent proteases
Calpains
CAPN1
CAPN2
CAPN3
CAPN4
CAPN5
CAPN6
CAPN7
CAPN8
CAPN9
CAPN10
Indirect regulators
Calcitonin
Parathyroid hormone
Vitamin D
Vitamin K
Extracellular chelators
Extracellular matrix proteins
Fibulins
FBLN1
FBLN2
FBLN3
FBLN4
FBLN5
Hemicentin 1
Matrix gla protein
Osteonectin
SIBLINGs
Bone sialoprotein
Dentin matrix phosphoprotein
Dentin sialophosphoprotein
Osteopontin
Secreted hormones
Osteocalcin
Calcium-binding domains
C2 domain
Cadherin
C-type lectin
EF hand
EGF-like domain
Gla domain
UpToDate Contents
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5. 成人における重度非労作性高熱（古典的熱中症） severe nonexertional hyperthermia classic heat stroke in adults
English Journal
RyR1 Deficiency in Congenital Myopathies Disrupts Excitation-Contraction Coupling.
Zhou H, Rokach O, Feng L, Munteanu I, Mamchaoui K, Wilmshurst JM, Sewry C, Manzur AY, Pillay K, Mouly V, Duchen M, Jungbluth H, Treves S, Muntoni F.SourceDubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, UK.
Human mutation.Hum Mutat.2013 Jul;34(7):986-96. doi: 10.1002/humu.22326. Epub 2013 Apr 17.
In skeletal muscle, excitation-contraction (EC) coupling is the process whereby the voltage-gated dihydropyridine receptor (DHPR) located on the transverse tubules activates calcium release from the sarcoplasmic reticulum by activating ryanodine receptor (RyR1) Ca(2+) channels located on the termina
Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis.
Dlamini N, Voermans NC, Lillis S, Stewart K, Kamsteeg EJ, Drost G, Quinlivan R, Snoeck M, Norwood F, Radunovic A, Straub V, Roberts M, Vrancken AF, van der Pol WL, de Coo RI, Manzur AY, Yau S, Abbs S, King A, Lammens M, Hopkins PM, Mohammed S, Treves S, Muntoni F, Wraige E, Davis MR, van Engelen B, Jungbluth H.SourceDepartment of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK.
Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis
Exon skipping as a therapeutic strategy applied to a RyR1 mutation with pseudo-exon inclusion causing a severe core myopathy.
Rendu J, Brocard J, Denarier E, Monnier N, Pietri-Rouxel F, Beley C, Roux-Buisson N, Gilbert-Dussardier B, Perez MJ, Romero NB, Garcia L, Lunardi J, Fauré J, Fourest-Lieuvin A, Marty I.SourceGIN, U836, La Tronche, France ; JRendu@chu-grenoble.fr.
Human gene therapy.Hum Gene Ther.2013 Jun 27. [Epub ahead of print]
Central Core Disease is a myopathy often arising from mutations in the RYR1 gene, encoding the sarcoplasmic reticulum calcium release channel RyR1. No treatment is currently available for this disease. We studied the pathological situation of a severely affected child with two recessive mutations, w
Nitric oxide-induced calcium release: activation of type 1 ryanodine receptor by endogenous nitric oxide.
Kakizawa Sho,Yamazawa Toshiko,Iino Masamitsu
Channels 7(1), 1-5, 2013-01-01
… NICR is evoked by neuronal activity, is dependent on S-nitrosylation of type 1 RyR (RyR1) and is involved in the induction of long-term potentiation (LTP) of cerebellar synapses. … In this addendum, we examined whether peroxynitrite, which is produced by the reaction of nitric oxide with superoxide, may also have an effect on the Ca2+ release via RyR1 and the cerebellar LTP. …
… Reversible S-nitrosylation of type 1 RyR (RyR1) triggers this Ca(2+) release. … These findings suggest that NICR via RyR1 plays a regulatory role in the physiological and pathophysiological functions of the brain. …
The RYR1 gene provides instructions for making a protein called ryanodine receptor 1. This protein is part of a family of ryanodine receptors, which form channels that transport positively charged calcium atoms (ions ...
