Ryanodine receptor

Overview: The ryanodine receptors (RyRs) are found on intracellular Ca²⁺ storage/release organelles. The family of RyR genes encodes three highly related Ca²⁺ release channels: RyR1, RyR2 and RyR3, which assemble as large tetrameric structures. These RyR channels are ubiquitously expressed in many types of cells and participate in a variety of important Ca²⁺ signalling phenomena (neurotransmission, secretion, etc.). In addition to the three mammalian isoforms described below, various non-mammalian isoforms of the RyR have been identified, and these are discussed in Sutko and Airey (1996). The function of the RyR channels may also be influenced by closely associated proteins such as the tacrolimus (FK506)-binding protein, calmodulin (Yamaguchi et al., 2003), triadin, calsequestrin, junctin and sorcin, and by protein kinases and phosphatases.

Nomenclature	RyR1	RyR2	RyR3
Ensembl ID	ENSG00000196218	ENSG00000198626	ENSG00000198838
Endogenous activators	Depolarization via DHP receptor, cytosolic Ca2+ (µM), cytosolic ATP (mM), luminal Ca2+, calmodulin at low cytosolic Ca2+, CaM kinase, PKA	Cytosolic Ca2+ (µM), cytosolic ATP (mM), luminal Ca2+, CaM kinase, PKA	Cytosolic Ca2+ (µM), cytosolic ATP (mM), calmodulin at low cytosolic Ca2+
Pharmacological activators	Ryanodine (nM–µM), caffeine (mM), suramin (µM)	Ryanodine (nM–µM), caffeine (mM), suramin (µM)	Ryanodine (nM–µM), caffeine (mM)
Antagonists	Cytosolic Ca2+(>100 µM), cytosolic Mg2+ (mM), calmodulin at high cytosolic Ca2+ dantrolene	Cytosolic Ca2+(>1 mM), cytosolic Mg2+ (mM), calmodulin at high cytosolic Ca2+	Cytosolic Ca2+(>1 mM), cytosolic Mg2+ (mM), calmodulin at high cytosolic Ca2+, dantrolene
Channel blockers	Ryanodine (>100 µM), ruthenium red, procaine	Ryanodine (>100 µM), ruthenium red, procaine	Ruthenium red
Functional characteristics	Ca2+: (PCa/PK∼ 6) single-channel conductance: ∼90 pS (50 mM Ca2+), 770 pS (200 mM K+)	Ca2+: (PCa/PK∼ 6) single-channel conductance: ∼90 pS (50 mM Ca2+), 720 pS (210 mM K+)	Ca2+: (PCa/PK∼ 6) single-channel conductance: ∼140 pS (250 mM Ca2+), 777 pS (250 mM K+)

The modulators of channel function included in this table are those most commonly used to identify ryanodine-sensitive Ca²⁺ release pathways. Numerous other modulators of RyR/channel function can be found in the reviews listed below. The absence of a modulator of a particular isoform of receptor indicates that the action of that modulator has not been determined, not that it is without effect. The potential role of cyclic ADP ribose as an endogenous regulator of RyR channels is controversial. A region of RyR likely to be involved in ion translocation and selection has been identified (Zhao et al., 1999; Gao et al., 2000).

Further Reading

Berridge M, Bootman MD, Roderick HL (2003). Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol4: 517–529.

Berridge MJ, Lipp P, Bootman MD (2000). The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol1: 11–21.

Bouchard R, Pattarini E, Geiger JD (2003). Presence and functional significance of presynaptic ryanodine receptors. Prog Neurobiol69: 391–418.

Bolton TB (2006). Calcium events in smooth muscles and their interstitial cells: physiological roles of sparks. J Physiol570: 5–11.

Collin T, Marty A, Llano I (2005). Presynaptic calcium stores and synaptic transmission. Curr Opin Neurobiol15: 275–281.

Dulhunty AF, Beard NA, Pouliquin P, Casarotto MG (2007). Agonists and antagonists of the cardiac ryanodine receptor: potential therapeutic agents? Pharmacol Ther113: 247–263.

Eisner A, Diaz ME, O'Neill SC, Trafford AW (2004). Physiology and pathological modulation of ryanodine receptor function in cardiac muscle. Cell Calcium35: 583–589.

Fill M, Copello JA (2002). Ryanodine receptor calcium release channels. Physiol Rev82: 893–922.

Hamilton SL, Serysheva II (2009). Ryanodine receptor structure: progress and challenges. J Biol Chem284: 4047–4051.

Meissner G (2004). Molecular regulation of cardiac ryanodine receptor ion channel. Cell Calcium35: 621–628.

Nahorski SR (2006). Pharmacology of intracellular signalling pathways. Br J Pharmacol147 (Suppl. 1): S38–S45.

Ross D, Sorrentino V (2002). Molecular genetics of ryanodine receptors Ca²⁺ release channels. Cell Calcium32: 307–319.

Shoshan-Barmatz V, Ashley RH (1998). The structure, function and cellular regulation of ryanodine-sensitive Ca²⁺-release channels. Int Rev Cytol183: 185–270.

Sitsapesan R, Williams AJ (1998). The Structure and Function of Ryanodine Receptors. Imperial College Press: London.

Sutko JL, Airey JA (1996). Ryanodine Ca²⁺ release channels: does diversity in form equal diversity in function? Physiol Rev76: 1027–1071.

Sutko JL, Airey JA, Welch W, Ruest L (1997). The pharmacology of ryanodine and related compounds. Pharmacol Rev49: 53–98.

Taur Y, Frishman WH (2005). The cardiac ryanodine receptor (RyR2) and its role in heart disease. Cardiol Rev13: 142–146.

Verkhratsky A (2005) Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev85: 201–279.

Zucchi, R, Ronca-Testoni S (1997). The sarcoplasmic reticulum Ca²⁺ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states. Pharmacol Rev49: 1–51.