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.
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.
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).
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).
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
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.
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.
^ Vites A, Pappano A (1994). "Distinct modes of inhibition by ruthenium red and ryanodine of calcium-induced calcium release in avian atrium". J Pharmacol Exp Ther268 (3): 1476-84. PMID 7511166.
^ Xu L, Tripathy A, Pasek D, Meissner G. "Potential for pharmacology of ryanodine receptor/calcium release channels". Ann N Y Acad Sci853: 130-48. PMID 10603942.
^ Wang Y, Zheng Y, Mei Q, Wang Q, Collier M, Fleischer S, Xin H, Kotlikoff M (2004). "FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells". Am J Physiol Cell Physiol286 (3): C538-46. PMID 14592808.
^ Tu J, Xiao B, Yuan J, Lanahan A, Leoffert K, Li M, Linden D, Worley P (1998). "Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors". Neuron21 (4): 717-26. PMID 9808459.