Ryanodine receptor

Ryanodine receptors (RyRs) form a class of calcium channels in various forms of muscle and other excitable animal tissue. It is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.

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Etymology

The receptors are named after the plant alkaloid ryanodine, to which they show high affinity:

Isoforms

There are multiple isoforms of ryanodine receptors:

• RyR1 is primarily expressed in skeletal muscle
• RyR2 in myocardium (heart muscle)
• A third form, RyR3, is expressed more widely, but especially in the brain^[1].
• There is also a fourth form found only in fish.

Physiology

Ryanodine receptors mediate the release of calcium ions from the sarcoplasmic reticulum, an essential step in muscle contraction. In skeletal muscle, it is thought that activation occurs via a physical coupling to the L-type calcium channel, whereas, in cardiac muscle, the primary mechanism is calcium-induced calcium release ^[2].

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 ^[3].

Ryanodine receptors are similar to the inositol triphosphate (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]

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 TRK, which leads to the production of inositol triphosphate, which in turn activates the InsP₃ receptor.

Pharmacology

• Antagonists:^[4]
  • 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:^[5]
  • 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 12kd 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).^[6]

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^[7]

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 millimolar) 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.^[1] 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, and thus may play a role in the pathogenesis of neurodegenerative diseases, like Alzheimer's disease.

The presence of antibodies against ryanodine receptors in blood serum has also been associated with myasthenia gravis.

References