Cytoplasmic face of phosphorylated RyR2 in open conformation. PDB: 7U9R
Ryanodine receptors (RyR) make up a class of high-conductance, intracellular calcium channels present in various forms, such as animal muscles and neurons.[1] There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in various signaling pathways involving calcium release from intracellular organelles.[2]
Ryanodine receptors are multidomain homotetramers which regulate intracellular calcium ion release from the sarcoplasmic and endoplasmic reticula.[3] They are the largest known ion channels, with weights exceeding 2 megadaltons, and their structural complexity enables a wide variety of allosteric regulation mechanisms.[4][5]
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][6]
Etymology
The ryanodine receptors are named after the plant alkaloidryanodine which shows a high affinity to them.
Isoforms
There are multiple isoforms of ryanodine receptors:
RyR2 is primarily expressed in myocardium (heart muscle)
the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.
RyR3 is expressed more widely, but especially in the brain.[7]
It is involved in neuroprotection, memory, pain modulation, and social behavior.[8]
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 inositol trisphosphate (IP3) receptors.
It has been shown that calcium release from a number of ryanodine receptors in a RyR cluster results in a spatiotemporally-restricted rise in cytosolic calcium that can be visualized as a calcium spark.[10] Calcium release from RyR has been shown to regulate ATP production in heart and pancreas cells.[11][12][13]
Ryanodine receptors are similar to the inositol trisphosphate (IP3 or InsP3) 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 indicates that a plot of opening probability for RyR as a function of Ca2+ concentration is a bell-curve.[14] 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).[15]
The localized and time-limited activity of Ca2+ in the cytosol is also called a Ca2+ wave. The propagation of the wave is accomplished by the feedback mechanism of the ryanodine receptor. The activation of phospholipase C by GPCR or RTK triggers the production of inositol trisphosphate, which activates of the InsP3 receptor.
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).[18]
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[19]
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.
Diamide insecticide
The diamides, an important class of insecticide making up 13% of the insecticide market,[20] work by activating insect RyRs.[21]
Associated proteins
RyRs form docking platforms for a multitude of proteins and small molecule ligands.[1] Accessory proteins bind these channels and regulate their gating, localization, expression, and integration with cellular signaling in a tissue- and isoform-specific manner.
The cardiac-specific isoform (RyR2) is known to form a quaternary complex with luminal calsequestrin, junctin, and triadin.[22] Calsequestrin (CASQ) has multiple Ca2+ binding sites that bind with very low affinity, allowing easy ion release. It acts as RyR gate modulators by signaling when Ca2+ stores are full. Triadin and Junctin are sarcoplasmic reticulum (SR) membrane proteins that link RyRs to CASQ and also respond to Ca²⁺ store levels.[23]
Calmodulin (CaM) and S100A1 both bind the same site on RyRs (especially RyR1 and RyR2), but exert opposite effects: Ca²⁺-bound CaM inhibits RyRs while S100A1 enhances its opening. Expression levels and competition between these proteins tune RyR responses to Ca²⁺ signals.[8]
Role in disease
RyR1 mutations are associated with malignant hyperthermia and central core disease.[24] Mutant-type RyR1 receptors exposed to volatile anesthetics or other triggering agents can display an increased affinity for cytoplasmic Ca2+ at activating sites as well as a decreased cytoplasmic Ca2+ affinity at inhibitory sites.[25] The breakdown of this feedback mechanism causes uncontrolled release of Ca2+ into the cytoplasm, and increased ATP hydrolysis resulting from ATPase enzymes shuttling Ca2+ back into the sarcoplasmic reticulum leads to excessive heat generation.[26]
The presence of antibodies against ryanodine receptors in blood serum has also been associated with myasthenia gravis (i.e., MG).[1] Individuals with MG who have antibodies directed against ryanodine receptors typically have a more severe form of generalized MG in which their skeletal muscle weaknesses involve muscles that govern basic life functions.[29]
Sudden cardiac death in several young individuals in the Amish community (four of which were from the same family) was traced to homozygous duplication of a mutant RyR2 (Ryanodine Receptor) gene.[30] Normal (wild type) ryanodine receptors are involved in CICR in heart and other muscles, and RyR2 functions primarily in the myocardium (heart muscle).
As potential drug targets
The expression, distribution, and gating of RyRs are modified by cellular proteins, presenting an opportunity to develop new drugs that target RyR channel complexes by manipulating these proteins. Several drugs, such as FK506, rapamycin, and K201, can modify interactions between RyRs and their accessory proteins.[8]
↑ Santulli G, Lewis D, des Georges A, Marks AR, Frank J (2018). "Ryanodine Receptor Structure and Function in Health and Disease". In Harris JR, Boekema EJ (eds.). Membrane Protein Complexes: Structure and Function. Vol.87. Singapore: Springer Singapore. pp.329–352. doi:10.1007/978-981-10-7757-9_11. ISBN978-981-10-7756-2. PMC5936639. PMID29464565.{{cite book}}: |journal= ignored (help)
↑ Fabiato A (July 1983). "Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum". The American Journal of Physiology. 245 (1): C1-14. doi:10.1152/ajpcell.1983.245.1.C1. PMID6346892.
↑ Vites AM, Pappano AJ (March 1994). "Distinct modes of inhibition by ruthenium red and ryanodine of calcium-induced calcium release in avian atrium". The Journal of Pharmacology and Experimental Therapeutics. 268 (3): 1476–1484. doi:10.1016/S0022-3565(25)38589-7. PMID7511166.
↑ Wang YX, Zheng YM, Mei QB, Wang QS, Collier ML, Fleischer S, etal. (March 2004). "FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells". American Journal of Physiology. Cell Physiology. 286 (3): C538 –C546. doi:10.1152/ajpcell.00106.2003. PMID14592808. S2CID20900277.
↑ Meissner G (2002-11-01). "Regulation of mammalian ryanodine receptors". Frontiers in Bioscience: A Journal and Virtual Library. 7 (4) A899: d2072–2080. doi:10.2741/A899. ISSN1093-9946. PMID12438018.
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