Ryanodine receptors (RyR) make up a class of high-conductance, intracellularcalcium channels present in various forms, such as animalmuscles andneurons.^[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 extendedα-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]

The ryanodine receptors are named after the plantalkaloidryanodine which shows a high affinity to them.

There are multiple isoforms of ryanodinereceptors:

• RyR1 is primarily expressed inskeletal muscle
  • It is essential forexcitation-contraction coupling
• RyR2 is primarily expressed inmyocardium (heart muscle)
  • the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.
• RyR3 is expressed more widely, but especially in thebrain.^[7]
  • It is involved inneuroprotection, 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 organismsDrosophila melanogaster (fruitfly) andCaenorhabditis 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.

Ryanodine receptors mediate the release ofcalcium ions from thesarcoplasmic reticulum andendoplasmic reticulum, an essential step inmuscle contraction.^[1] Inskeletal muscle, activation of ryanodine receptors occurs via a physical coupling to thedihydropyridine receptor (a voltage-dependent,L-type calcium channel), whereas incardiac muscle, the primary mechanism of activation iscalcium-induced calcium release, which causes calcium outflow from the sarcoplasmic reticulum.^[9]

It has been shown thatcalcium 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 acalcium 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 theinositol trisphosphate (IP₃ or InsP₃) receptor, and stimulated to transport Ca²⁺ into the cytosol by recognizing Ca²⁺ on itscytosolic side, thus establishing apositive 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 asstore overload-induced calcium release (SOICR).^[15]

RyRs are especially important inneurons andmuscle cells. Inheart andpancreas 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 aCa²⁺ wave. The propagation of the wave is accomplished by the feedback mechanism of the ryanodine receptor. The activation ofphospholipase C byGPCR orRTK triggers the production of inositol trisphosphate, which activates of the InsP₃ receptor.

• Antagonists:^[16]
  • 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:^[17]
  • Agonist:4-chloro-m-cresol andsuramin are direct agonists, i.e., direct activators.
  • Xanthines likecaffeine andpentifylline 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 makingFKBP12.6 (12.6 kilodaltonFK506 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: dimerizedHomer physical tether linking inositol trisphosphate receptors (IP3R) and ryanodine receptors on the intracellular calcium stores with cell surfacegroup 1 metabotropic glutamate receptors and theAlpha-1D adrenergic receptor^[19]

The plant alkaloidryanodine, 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 isuse-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.

Thediamides, an important class ofinsecticide making up 13% of the insecticide market,^[20] work by activating insect RyRs.^[21]

RyRs form docking platforms for a multitude of proteins and small moleculeligands.^[1] Accessory proteins bind these channels and regulate their gating, localization, expression, and integration with cellular signaling in a tissue- and isoform-specific manner.

FK506-Binding Proteins (FKBP12 / FKBP12.6) — akaCalstabin-1 and Calstabin-2 — stabilize the closed state of RyRs, preventing pathological Ca²⁺ leak.^[8]

The cardiac-specific isoform (RyR2) is known to form a quaternary complex with luminalcalsequestrin,junctin, andtriadin.^[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 aresarcoplasmic reticulum (SR) membrane proteins that link RyRs to CASQ and also respond to Ca²⁺ store levels.^[23]

Calmodulin (CaM) andS100A1 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]

RyR1mutations are associated withmalignant hyperthermia andcentral 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]

RyR2 mutations play a role in stress-inducedpolymorphicventricular tachycardia (a form ofcardiac arrhythmia) andARVD.^[7] It has also been shown that levels of type RyR3 are greatly increased inPC12 cells overexpressing mutant humanPresenilin 1, and in brain tissue in knockin mice that express mutant Presenilin 1 at normal levels,^[27] and thus may play a role in the pathogenesis ofneurodegenerative diseases, likeAlzheimer's disease.^[28]

The presence ofantibodies against ryanodine receptors inblood serum has also been associated withmyasthenia 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).

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]

• Diamide, a class of insecticide that act through ryanodine receptors
• Neuromuscular junction
• Dihydropyridine receptor

• Ryanodine+Receptor at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• Genes on human chromosome 19
• Genes on human chromosome 1
• Genes on human chromosome 15
• Transmembrane receptors
• Calcium channels
• Membrane channels

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