doi: 10.1161/01.RES.0000030194.38795.86
© 2002 American Heart Association, Inc.
Editorials |
Leaky "Feet" and Sudden Death
From the Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Department of Anesthesia, Harvard Medical School, Boston, Mass.
Correspondence to P.D. Allen, MD, PhD, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail allen{at}zeus.bwh.harvard.edu
Key Words: sarcoplasmic reticulum • ryanodine receptors • malignant hyperthermia • ventricular tachycardia • sudden death
Increases in intracellular Ca2+ are crucial signaling events in many cell types. The cardiac isoform of the (sarco)endoplasmic reticulum Ca2+ release channel or ryanodine receptor (RyR2) is an important component of this signaling pathway in a wide variety of both excitable (nerve, smooth muscle, and heart) and nonexcitable (parotid, pancreas, and adrenal medulla) cells and is a critical component of excitation-contraction coupling in the heart.1,2 The absence of RyR2 in knockout mice leads to an early embryonic lethal phenotype because its function is essential for regulation of the intrinsic beating rate, and this early lethality has prevented studying its absence in other cell types.3
Unlike skeletal muscle, where excitation-contraction coupling is mediated through a mechanical coupling between its RyR isoform, RyR1, and the skeletal isoform of the sarcolemmal slow voltage-gated Ca2+ channel (dihydropyridine receptor, DHPR), in cardiac muscle, Ca2+ release through RyR2 is caused by the inward Ca2+ flux through the cardiac DHPR via Ca2+-induced Ca2+ release (CICR). It also appears that, at least in heart, RyR2 is part of a larger macromolecular complex containing phosphorylases, phosphatases, and the immunophilin FKBP12.6, which regulate the level of CICR.4,5
Because of its large size (>200-kB gene, 
15-kB mRNA), it is not surprising that the ryanodine receptor is a likely target for mutation. There are >30 reported missense mutations in the RyR1 gene that have been associated with alterations of Ca2+ homeostasis and are the cause of central core disease (CCD) and malignant hyperthermia (MH).6–10 More recently, 11 missense mutations have been associated with a group of closely associated cardiomyopathies that are characterized by early sudden death: arrhythmogenic right ventricular cardiomyopathy (ARVD2), familial polymorphic ventricular tachycardia, and catecholaminergic polymorphic ventricular tachycardia.9,11,12 Interestingly, the RyR2 mutations associated with cardiomyopathies are clustered in the same hot spots as the RyR1 mutations associated with MH and CCD (see Figure). These skeletal RyR channelopathies are associated with high resting myoplasmic Ca2+, increased sensitivity to caffeine and halothane, reduced internal Ca2+ stores, and a reduced sensitivity to Ca2+ and Mg2+ inhibition.13,14 This has led to the hypothesis that the cardiac RyR channelopathies are likely to result in an increased diastolic Ca2+ and potential arrhythmogenic Ca2+ waves.
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In this issue of Circulation Research, Jiang et al15 report on the possible mechanism for catecholaminergic polymorphic ventricular tachycardia, examining the biophysics of heterologously expressed RyR2 channels carrying one of the reported clinical mutations. The authors demonstrate that substitution of an arginine at position 4496 with either a neutral (A) polar (C) or negatively charged (E) amino acid progressively increased the open probability of RyR2 at low Ca2+ concentrations. The clinical mutation R4496C was also shown to induce a higher frequency of spontaneous Ca2+ waves in transfected cells than wild type. This suggests the possibility that the mutated channels increased activity of the channel during diastole in the heart and increased the Ca2+ load thereby increasing the frequency of propagated Ca2+ waves leading to arrhythmias. The hypothesis that this syndrome has a similar phenotype to MH/CCD is supported by the fact that, similar to the findings in the present study, Yang et al16 have seen increased ryanodine binding at very low Ca2+ concentrations in 6 human MH/CCD mutations expressed in dyspedic myotubes. One difference that separates R4496C from the RyR1 MH/CCD mutations is in its lack of difference from wild type in terms of Ca2+ inhibition. This, however, may be due to the fact that RyR2 has an intrinsically lower sensitivity to Ca2+ inhibition than RyR1 and this masked the potential difference.
The work of Jiang et al15 is a great beginning toward our understanding the mechanisms that cause this syndrome. Hopefully, it is only a beginning. Unfortunately, HEK cells are not heart cells, and they lack both critical components that regulate RyR2 in vivo and regular depolarization with Ca2+ entry. What now cries out to be done is to repeat the present experiments on least representative mutations from the other two hot spots, including evaluation of the effect of the mutation on total internal Ca2+ stores to complete the analogy with MH/CCD. Then, it will be crucial (1) to express these and other hot spot mutants in neonatal cardiac cells and examine the possible alterations in spontaneous Ca2+ release activity and sparks in vitro and (2) to create either transgenic or knock-in mice expressing the mutated proteins and examine their phenotype in vivo.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Giannini G, Sorrentino V. Molecular structure and tissue distribution of ryanodine receptors calcium channels. Med Res Rev. 1995; 15: 313–323.[CrossRef][Medline] [Order article via Infotrieve]
2. Sorrentino V. The ryanodine receptor family of intracellular calcium release channels. Adv Pharmacol. 1995; 33: 67–90.[CrossRef][Medline] [Order article via Infotrieve]
3. Yang H-T, Tweedie D, Wang S, Guia A, Vinogradova T, Bogdanov K, Allen PD, Stern MD, Lakatta EG, Boheler KR. The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development. Proc Natl Acad Sci U S A. June 27, 2002; 10.1073/pnas.142651999. Available at: http://www.pnas.org. Accessed July 9, 2002.
4. Marx SO, Reiken S, Hisamatsu Y, Gaburjakova M, Gaburjakova J, Yang YM, Rosemblit N, Marks AR. Phosphorylation-dependent regulation of ryanodine receptors: a novel role for leucine/isoleucine zippers. J Cell Biol. 2001; 153: 699–708.
5. Marks AR, Reiken S, Marx SO. Progression of heart failure: is protein kinase A hyperphosphorylation of the ryanodine receptor a contributing factor? Circulation. 2002; 105: 272–275.
6. Brandt A, Schleithoff L, Jurkat-Rott K, Klingler W, Baur C, Lehmann-Horn F. Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test. Hum Mol Genet. 1999; 8: 2055–2062.
7. Deufel T, Sudbrak R, Feist Y, Rubsam B, Du Chesne I, Schafer KL, Roewer N, Grimm T, Lehmann-Horn F, Hartung EJ, et al. Discordance, in a malignant hyperthermia pedigree, between in vitro contracture-test phenotypes and haplotypes for the MHS1 region on chromosome 19q12-13.2, comprising the C1840T transition in the RYR1 gene. Am J Hum Genet. 1995; 56: 1334–1342.[Medline] [Order article via Infotrieve]
8. Keating KE, Quane KA, Manning BM, Lehane M, Hartung E, Censier K, Urwyler A, Klausnitzer M, Muller CR, Heffron JJ, et al. Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees. Hum Mol Genet. 1994; 3: 1855–1858.
9. Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, Larderet G, Brahmbhatt B, Brown K, Bauce B, Muriago M, Basso C, Thiene G, Danieli GA, Rampazzo A. 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: 189–194.
10. Tong J, Oyamada H, Demaurex N, Grinstein S, McCarthy TV, MacLennan DH. Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. J Biol Chem. 1997; 272: 26332–26339.
11. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino VV, Danieli GA. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001; 103: 196–200.
12. Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, Donarum EA, Marino M, Tiso N, Viitasalo M, Toivonen L, Stephan DA, Kontula K. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation. 2001; 103: 485–490.
13. Lopez JR, Gerardi A, Lopez MJ, Allen PD. Effects of dantrolene on myoplasmic free [Ca2+] measured in vivo in patients susceptible to malignant hyperthermia. Anesthesiology. 1992; 76: 711–719.[Medline] [Order article via Infotrieve]
14. Mickelson JR, Louis CF. Malignant hyperthermia: excitation-contraction coupling, Ca2+ release channel, and cell Ca2+ regulation defects. Physiol Rev. 1996; 76: 537–592.
15. Jiang D, Xiao B, Zhang L, Chen SRW. Enhanced basal activity of a cardiac Ca2+ release channel (ryanodine receptor) mutant associated with ventricular tachycardia and sudden death. Circ Res. 2002; 91: 218–225.
16. Yang T, Fessenden JD, Ta TA, Mukherjee S, Pessah IN, Allen PD. Caffeine, 4-CMC and K+ sensitivity of intracellular Ca2+ release is altered by six RyR-1 mutations associated with malignant hyperthermia. Biophys J. 2002; 82: 641a. Abstract.
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