Calcium release from intracellular stores plays an important role in the regulation of muscle contraction and electrical signals that determine the heart rhythm. The ryanodine receptor (RyR) is the major calcium (Ca2+) release channel required for excitation-contraction coupling in the heart. Recent studies have demonstrated that RyR are macromolecular complexes comprising of 4 pore-forming channel subunits, each of which is associated with regulatory subunits. Clinical and experimental studies over the past 5 years have provided compelling evidence that intracellular Ca2+ release channels play a pivotal role in the development of cardiac arrhythmias and heart failure. Changes in the channel regulation and subunit composition are believed to cause diastolic calcium leakage from the sarcoplasmic reticulum, which could trigger arrhythmias and weaken cardiac contractility. Therefore, cardiac RyR have emerged as potential therapeutic targets for the treatment of heart disease. Consequently, there is a strong desire to identify and/or develop novel pharmacological agents that may target these Ca2+ signaling pathways. Pharmacological agents known to modulate RyR in the heart, and their potential application towards the treatment of heart disease are discussed in this review.
Franzini-Armstrong C, Protasi F, Ramesh V . Comparative ultrastructure of Ca2+ release units in skeletal and cardiac muscle. Ann N Y Acad Sci 1998; 853: 20–30.
Bers DM, Guo T . Calcium signaling in cardiac ventricular myocytes. Ann N Y Acad Sci 2005; 1047: 86–98.
Du GG, MacLennan DH . Topology and transmembrane organization of ryanodine receptors. In: Wehrens XH, Marks AR, editors. Ryanodine receptors: structure, function and dysfunction in clinical disease; v 254. New York: Springer; 2005. p 9–23.
Wehrens XHT, Lehnart SE, Marks AR . Intracellular calcium release channels and cardiac disease. Annu Rev Physiol 2005; 67: 69–98.
Williams AJ, West DJ, Sitsapesan R . Light at the end of the Ca2+-release channel tunnel: structures and mechanisms involved in ion translocation in ryanodine receptor channels. Q Rev Biophys 2001; 34: 61–104.
Lehnart SE, Huang F, Marx SO, Marks AR . Immunophilins and coupled gating of ryanodine receptors. Curr Top Med Chem 2003; 3: 1383–91.
Cheng H, Lederer WJ, Cannell MB . Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science 1993; 262: 740–4.
Yano M, Yamamoto T, Ikeda Y, Matsuzaki M . Mechanisms of disease: ryanodine receptor defects in heart failure and fatal arrhythmia. Nat Clin Pract Cardiovasc Med 2006; 3: 43–52.
Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001; 10: 189–94.
Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001; 103: 196–200.
Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 2001; 103: 485–90.
Wehrens XH . The molecular basis of catecholaminergic polymorphic ventricular tachycardia: what are the different hypotheses regarding mechanisms? Heart Rhythm 2007; in press.
Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): Defective regulation in failing hearts. Cell 2000; 101: 365–76.
Yano M, Ono K, Ohkusa T, Suetsugu M, Kohno M, Hisaoka T, et al. Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca2+ leak through ryanodine receptor in heart failure. Circulation 2000; 102: 2131–6.
Phrommintikul A, Chattipakorn N . Roles of cardiac ryanodine receptor in heart failure and sudden cardiac death. Int J Cardiol 2006; 112: 142–52.
Wehrens XH, Lehnart SE, Reiken S, Vest JA, Wronska A, Marks AR . Ryanodine receptor/calcium release channel PKA phosphorylation: a critical mediator of heart failure progression. Proc Natl Acad Sci USA 2006; 103: 511–8.
Bers DM, Eisner DA, Valdivia HH . Sarcoplasmic reticulum Ca2+ and heart failure: roles of diastolic leak and Ca2+ transport. Circ Res 2003; 93: 487–90.
Bers DM . Cardiac ryanodine receptor phosphorylation: target sites and functional consequences. Biochem J 2006; 396: 1–3.
Wehrens XH, Marks AR . Novel therapeutic approaches for heart failure by normalising calcium cycling. Nat Rev Drug Discov 2004; 3: 565–73.
Zucchi R, Ronca-Testoni S . The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states. Pharmacol Rev 1997; 49: 1–51.
Meissner G . Adenine nucleotide stimulation of Ca2+-induced Ca2+ release in sarcoplasmic reticulum. J Biol Chem 1984; 259: 2365–74.
Sitsapesan R, Williams AJ . Mechanisms of caffeine activation of single calcium-release channels of sheep cardiac sarcoplasmic reticulum. J Physiol 1990; 423: 425–39.
Seifert J, Casida JE . Ca2+-dependent ryanodine binding site: soluble preparation from rabbit cardiac sarcoplasmic reticulum. Biochim Biophys Acta 1986; 861: 399–405.
McGarry SJ, Williams AJ . Activation of the sheep cardiac sarcoplasmic reticulum Ca(2+)-release channel by analogues of sulmazole. Br J Pharmacol 1994; 111: 1212–20.
Tinker A, Sutko JL, Ruest L, Deslongchamps P, Welch W, Airey JA, et al. Electrophysiological effects of ryanodine derivatives on the sheep cardiac sarcoplasmic reticulum calcium-release channel. Biophys J 1996; 70: 2110–19.
McGarry SJ, Williams AJ . Digoxin activates sarcoplasmic reticulum Ca(2+)-release channels: a possible role in cardiac inotropy. Br J Pharmacol 1993; 108: 1043–50.
Sagawa T, Sagawa K, Kelly JE, Tsushima RG, Wasserstrom JA . Activation of cardiac ryanodine receptors by cardiac glycosides. Am J Physiol Heart Circ Physiol 2002; 282: H1118–26.
Sitsapesan R, Williams AJ . Modification of the conductance and gating properties of ryanodine receptors by suramin. J Membr Biol 1996; 153: 93–103.
Hill AP, Kingston O, Sitsapesan R . Functional regulation of the cardiac ryanodine receptor by suramin and calmodulin involves multiple binding sites. Mol Pharmacol 2004; 65: 1258–68.
Carrier L, Villaz M, Dupont Y . Abnormal rapid Ca2+ release from sarcoplasmic reticulum of malignant hyperthermia susceptible pigs. Biochim Biophys Acta 1991; 1064: 175–83.
Beltran M, Bull R, Donoso P, Hidalgo C . Ca2+-and pH-dependent halothane stimulation of Ca2+ release in sarcoplasmic reticulum from frog muscle. Am J Physiol 1996; 271: C540–6.
Connelly TJ, Coronado R . Activation of the Ca2+ release channel of cardiac sarcoplasmic reticulum by volatile anesthetics. Anesthesiology 1994; 81: 459–69.
Hanouz JL, Massetti M, Guesne G, Chanel S, Babatasi G, Rouet R, et al. In vitro effects of desflurane, sevoflurane, isoflurane, and halothane in isolated human right atria. Anesthesiology 2000; 92: 116–24.
Herrmann-Frank A, Richter M, Sarkozi S, Mohr U, Lehmann-Horn F . 4-Chloro-m-cresol, a potent and specific activator of the skeletal muscle ryanodine receptor. Biochim Biophys Acta 1996; 1289: 31–40.
George CH, Higgs GV, Lai FA . Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circ Res 2003; 93: 531–40.
Gurrola GB, Zhu X, Valdivia HH . Scorpion peptides as high-affinity probes of ryanodine receptor function. In: Wehrens XH, Marks AR, editors. Ryanodine receptors: structure, function, and dysfunction in clinical disease. New York: Springer; 2005. p 191–200.
Valdivia HH, Kirby MS, Lederer WJ, Coronado R . Scorpion toxins targeted against the sarcoplasmic reticulum Ca2+-release channel of skeletal and cardiac muscle. Proc Natl Acad Sci USA 1992; 89: 12185–9.
Tripathy A, Resch W, Xu L, Valdivia HH, Meissner G . Imperatoxin A induces subconductance states in Ca2+ release channels (ryanodine receptors) of cardiac and skeletal muscle. J Gen Physiol 1998; 111: 679–90.
Zamudio FZ, Conde R, Arevalo C, Becerril B, Martin BM, Valdivia HH, et al. The mechanism of inhibition of ryanodine receptor channels by imperatoxin I, a heterodimeric protein from the scorpion Pandinus imperator. J Biol Chem 1997; 272: 11886–94.
Kaftan E, Marks AR, Ehrlich BE . Effects of rapamycin on ryanodine receptor/Ca2+ release channels from cardiac muscle. Circ Res 1996; 78: 990–7.
Atkison P, Joubert G, Barron A, Grant D, Paradis K, Seidman E, et al. Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients. Lancet 1995; 345: 894–6.
Smith JS, Coronado R, Meissner G . Sarcoplasmic reticulum contains adenine nucleotide-activated calcium channels. Nature 1985; 316: 446–9.
Ma J . Block by ruthenium red of the ryanodine-activated calcium release channel of skeletal muscle. J Gen Physiol 1993; 102: 1031–56.
Chen SR, MacLennan DH . Identification of calmodulin-, Ca (2+)-, and ruthenium red-binding domains in the Ca2+ release channel (ryanodine receptor) of rabbit skeletal muscle sarcoplasmic reticulum. J Biol Chem 1994; 269: 22698–704.
Parness J . The dantrolene binding site on RyR1. In: Wehrens XH, Marks AR, editors. Ryanodine receptors: structure, function and dysfunction in clinical disease. New York: Springer; 2005. p 243–51.
Kobayashi S, Bannister ML, Gangopadhyay JP, Hamada T, Parness J, Ikemoto N . Dantrolene stabilizes domain interactions within the ryanodine receptor. J Biol Chem 2005; 280: 6580–7.
Besch HR, Shao CH, Bidasee KR . Ryanoids, receptor affinity and RyR channel subconductance. In: Wehrens XH, Marks AR, editors. Ryanodine receptors: structure, function and dysfunction in clinical disease. New York: Springer; 2005. p 179–89.
Sutko JL, Airey JA, Welch W, Ruest L . The pharmacology of ryanodine and related compounds. Pharmacol Rev 1997; 49: 53–98.
Nagasaki K, Fleischer S . Ryanodine sensitivity of the calcium release channel of sarcoplasmic reticulum. Cell Calcium 1988; 9: 1–7.
Shoshan-Barmatz V, Zchut S . The interaction of local anesthetics with the ryanodine receptor of the sarcoplasmic reticulum. J Membr Biol 1993; 133: 171–81.
Xu L, Jones R, Meissner G . Effects of local anesthetics on single channel behavior of skeletal muscle calcium release channel. J Gen Physiol 1993; 101: 207–33.
Overend CL, Eisner DA, O'Neill SC . The effect of tetracaine on spontaneous Ca2+ release and sarcoplasmic reticulum calcium content in rat ventricular myocytes. J Physiol 1997; 502: 471–9.
Venetucci LA, Trafford AW, Diaz ME, O'Neill SC, Eisner DA . Reducing ryanodine receptor open probability as a means to abolish spontaneous Ca2+ release and increase Ca2+ transient amplitude in adult ventricular myocytes. Circ Res 2006; 98: 1299–305.
Yano M, Kobayashi S, Kohno M, Doi M, Tokuhisa T, Okuda S, et al. FKBP 12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. Circulation 2003; 107: 477–84.
Wehrens XH, Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 2004; 304: 292–6.
Wehrens XH, Lehnart SE, Reiken S, van der Nagel R, Morales R, Sun J, et al. Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure. Proc Natl Acad Sci USA 2005; 102: 9607–12.
Brillantes AB, Ondrias K, Scott A, Kobrinsky E, Ondriasova E, Moschella MC, et al. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell 1994; 77: 513–23.
Wehrens XH, Lehnart SE, Huang F, Vest JA, Reiken SR, Mohler PJ, et al. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 2003; 113: 829–40.
Lehnart SE, Wehrens XHT, Laitinen PJ, Reiken SR, Deng SX, Chen Z, et al. Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak. Circulation 2004: 113–9.
Lehnart SE, Terrenoire C, Reiken S, Wehrens XH, Song LS, Tillman EJ, et al. Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias. Proc Natl Acad Sci USA 2006; 103: 7906–10.
Project supported by a scientist-development grant from the American Heart Association to Dr Xander H T WEHRENS (No 0535310-N) and the Caroline Weiss Law Fund for Research in Molecular Medicine.
About this article
Cite this article
Santonastasi, M., Wehrens, X. Ryanodine receptors as pharmacological targets for heart disease. Acta Pharmacol Sin 28, 937–944 (2007). https://doi.org/10.1111/j.1745-7254.2007.00582.x
- calcium release channel
- heart failure
- ryanodine receptor
EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2
Heart Rhythm (2018)
Acta Pharmacologica Sinica (2018)
Design, Synthesis, Structure-Activity Relationship and Insecticidal Activities of Trifluoromethyl-Containing Sulfiliminyl and Sulfoximinyl Phthalic Acid Diamide Structure
Chinese Journal of Chemistry (2014)
Pharmacology & Therapeutics (2013)
Heteromtoxin (HmTx), a novel heterodimeric phospholipase A2 from Heterometrus laoticus scorpion venom