Review articleRyanodine receptors and ventricular arrhythmias: Emerging trends in mutations, mechanisms and therapies
Introduction
“When the heart is diseased, its work is imperfectly performed: the vessels proceeding from the heart become inactive, so that you cannot feel them … if the heart trembles, has little power and sinks, the disease is advanced and death is near.”
This description, found in the Ebers Papyrus of Ancient Egypt pre-dating 1500 BC, is thought to be the earliest recorded account of ventricular fibrillation (VF). We now understand many of the molecular mechanisms that lead to the disruption of normal heart rhythm (arrhythmia) and its deterioration into a catastrophic breakdown of electrical synchrony (VF), the main cause of sudden death (SD). Despite our knowledge of many of these underlying defects, SD remains a major cause of mortality accounting for more than 750,000 deaths per year in Europe and the US (∼ 0.1% of total recorded deaths) [1].
Arrhythmia results from perturbation of the exquisitely controlled fluxes of Na+, K+ and Ca2+ ions both within cardiomyocytes and between the myocardium and the external milieu [2]. These ionic fluxes are highly interdependent, and thus localised disruption may exacerbate global ion flux imbalance resulting in the complete ablation of synchronous cardiac electrical activity. Over the last two decades, defective mechanisms in arrhythmogenic ion fluxes have been elucidated by functional characterisation of Na+ and K+ channels containing genetic mutations (‘channelopathies’) [3], [4], [5]. Currently, the genetic basis of Ca2+ handling dysfunction in arrhythmia is the focus of widespread attention, and is the subject of this review.
Intracellular and trans-plasmalemmal Ca2+ fluxes co-ordinate multiple facets of cardiac function [2], [6], [7], and precisely controlled Ca2+ cycling is a prerequisite for normal cardiac rhythm and contractility. Genetic mutations underlying malignant arrhythmias have recently been identified in cardiac Ca2+ channels including the L-type Ca2+ channel (LTCC, also termed the dihydropyridine receptor (DHPR), or more recently, Cav1.2) [8], [9], and ryanodine receptors (RyR2), large multi-functional Ca2+ release channels that are crucial for cardiac development and excitation–contraction (EC) coupling (for reviews see [10], [11], [12], [13], [14], [15]). However, unlike defects in Na+ and K+ ion handling, cellular Ca2+ dysfunction does not arise exclusively from Ca2+ channel abnormalities, but also from mutation-linked defects in intra-organellar Ca2+ storage (calsequestrin (CSQ), a major Ca2+ binding protein of the sarcoplasmic reticulum (SR) [16], [17], [18]), Ca2+ sequestration (phospholamban (PLB), a regulator of the SR Ca2+ ATPase (SERCA) [19], [20]) and the altered ‘shaping’ of cytoplasmic Ca2+ signals by cytoplasmic Ca2+ binding proteins involved in EC coupling (tropomyosin and troponin [21], [22], [23]). Furthermore, alterations in cytoskeletal architecture that disrupt the spatial organisation of Ca2+ signalling networks may be highly arrhythmogenic in the absence of any genetic defects in Ca2+ handling proteins per se [24]. Consequently, the complex physical and functional interplay between Ca2+ pumps, channels, stores and exchangers predicts that defects in diverse aspects of cardiomyocyte Ca2+ cycling directly contribute to an increased arrhythmogenic propensity.
In this review, we focus on mutations in RyR2 associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), and evaluate recent developments in mutation identification, our understanding of the mechanisms of RyR2 Ca2+ release dysfunction and provide an update on the therapeutic potential of RyR2-targeted anti-arrhythmic strategies.
Section snippets
RyR2 mutations: an etiopathological update
To date, sixty-nine RyR2 mutations have been identified that cause CPVT, a distinct form of early onset stress-induced malignant VT in which affected individuals present with syncopal events and with a distinctive pattern of stress-related, bi-directional VT in the absence of either structural heart disease or a prolonged QT interval [25]. The etiopathology and molecular genetics of RyR2 mutation-linked CPVT (CPVT1) have been reviewed [26], [27], [28], [29], [30], [31], but in view of the
The hot-spot nature of mutational loci: artefact or an important mechanistic clue?
The human RyR2 polypeptide (4967 amino acids) is organised as a complex series of discrete domains, with the carboxy-terminal transmembrane (TM) Ca2+ pore-forming domain comprising approximately 10% of the protein mass [62], [63], and the vast majority of the molecule orientated in the cytoplasm (Fig. 2). Accordingly, RyR2 are thought to act as co-incidence detectors in which cytoplasmic domains decode a multitude of cellular inputs (ambient Ca2+ environments, redox and metabolic status,
Mechanisms of mutation-linked RyR2 dysfunction
Analysis of mutational loci in the context of RyR2 structure-function (Fig. 2) reveals that mutations alter the ability of RyR2 to sense the intracellular environment. Furthermore, the structural and functional complexity of RyR2 predicts that arrhythmogenic mutation-linked defects occur in diverse aspects of channel functionality. The rapid progress that has been made in elucidating the mechanisms of mutation-linked defects in RyR2 modulation, together with the controversies that have arisen
Functional heterogeneity of mutation-linked Ca2+ release dysfunction
The data above serve to illustrate that although functional characterisation may permit mutations occurring in different domains to be grouped together according to similar mechanistic defects (e.g. defective intramolecular interaction), subtle but significant differences in the mode of channel dysfunction may be dependent on the mutational locus. This concept is corroborated by the finding that Ca2+ release dysfunction via RyR2 mutants exhibits pronounced functional heterogeneity [170], [194],
Mechanisms of CPVT arrhythmogenesis-converting Ca2+ dysfunction into electrical abnormalities
Despite the controversies highlighted above, a common feature has emerged in that all functionally characterised mutations mediate abnormal Ca2+ release following cellular stimulation, consistent with the stress-induced nature of the CPVT phenotype. The link between activated Ca2+ release dysfunction and the resultant electrical defects remains a central issue in CPVT1. The remarkable similarities between the electrical abnormalities associated with CPVT1 (including bi-directional and
Normalising RyR2 function in CPVT1
The unforeseeable risk of juvenile death associated with RyR2 mutations, compounded by a devastating phenotype in that the first event may be lethal, means that early diagnosis is essential. Despite the success of implantable cardioverter defibrillator (ICD) therapy, there are no optimal therapies to restore RyR2 dysfunction in arrhythmogenesis. The benefits of β-AR blockade in CPVT are substantial, although its efficacy is highly variable [1], [35], [36], [211], and thus the current complement
Summary
RyR2 mutations profoundly perturb the ability of RyR2 to decode its localised cellular environment, leading to inappropriate channel activity. Consequently, we propose that RyR2 mutations represent a disease of RyR2 cellular sensing via complex mechanisms that remain to be conclusively determined on a mutation-by-mutation basis. We further suggest that the mutation-linked arrhythmogenesis in CPVT1 arises via three main stages:
- 1)
mutations alter the ability of RyR2 to sense the cellular
Acknowledgments
The authors are supported by grants from the British Heart Foundation (BS/04/002, FS/04/088, PG/05/063, PG/05/077), the European Union (LSHM-CT-2005-018802) and Cardiff University. We thank Prof. Godfrey Smith and Dr. Christopher Loughrey for valuable discussions on K201.
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2018, Journal of Molecular and Cellular CardiologyCitation Excerpt :There is no evident genetic basis to explain the unusual recurrence of de novo mutations. In a review article by George et al., it was summarized that roughly 19% of all RyR2 mutations occur de novo, and that they are associated with an early age of onset, 8 ± 4 years compared with 20.2 ± 15.7 years for non de novo mutations [44]. In the present study, the proband demonstrates a de novo RyR2 A165D mutation, and the age of her first faint was 8 years.
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