Ryanodine Receptor Physiology and Its Role in Disease
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Abstract
The ryanodine receptors (RyRs) is the major intracellular Ca2+ release channel localized in the plasma membrane of the endoplasmatic/sarcoplasmatic reticulum. RyR-mediated Ca2+ release is crucial for every heart beat and skeletal muscle contraction and also important in learning and memory. Given the important role RyR has in physiological functions it is not surprising that dysregulation and impaired RyR channel function contributes to severe pathologies e.g. cardiac arrhythmias and Alzheimer’s disease. Mutations in the RyR channels are associated with a number of human disorders e.g. malignant hyperthermia (MH) and central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular dysplasia (ARVD). RyRs are modulated directly and indirectly by various ions, small molecules and proteins and RyR structure and function are expected to be defined within this macromolecular set of interactions. This article discusses the physiological function of RyR and examines its role in disorders and diseases.
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(8/22/2022, 12:02:03 AM)
“The ryanodine receptor (RyR) is the largest known ion channel; it is a homotetramer with a total mass of >2 MDa (each subunit is >550 kDa) [10–15]. RyR is localized in the plasma membrane of ER/SR and is a large conductance channel capable of creating rapid transient increase in cytosolic Ca2+ [16, 17]. Four-fifths of the RyR protein is cytoplasmic and remaining, one-fifth, consists of luminal and membrane spanning domains. Three mammalian isoforms of RyR have been isolated and the terminology, RyR1-3, is based on in which order the isoforms were isolated and tissue of initial purification. However, none of the isoforms are entirely tissuespecific; RyR1 is predominantly expressed in skeletal muscle and in cerebellar Purkinje neurons [11, 14, 18, 19]; RyR2 is greatly expressed in cardiac muscle [12, 13], and is considered to be the most abundant isoform in the brain [19, 20]; RyR3 was first identified in the brain and is mainly found in cortical and hippocampal regions involved in learning and memory [15, 19, 21]. RyR3 is also expressed in the diaphragm” Go to annotation (Lanner, 2012, p. 218)
“RyR exist predominantly in the closed state, but it has been noted that they open randomly in the absence of any stimulus. Furthermore, it has been determined that the number of open RyR, and the frequency and duration can be modulated by many physiological agents. RyRs are modulated directly and indirectly by DHPR and by various ions, small molecules and proteins (e.g. Ca2+, Mg2+, protein kinase A (PKA), FK506 binding proteins (FKBP12 and 12.6), calmodulin (CaM), Ca2+/CaMdependent kinase II (CaMKII), calsequestrin (CSQ), triadin, and junctin)” Go to annotation (Lanner, 2012, p. 218)
“RyR1-3 have a similar sequence homology (~65%), but despite this the isoforms differ markedly in their response to modulators. For instance, each subtype show different Ca2+ binding affinities with RyR1 > RyR2 > RyR3. RyR1 activity shows a bell-shaped response curve; activated by low Ca2+ concentrations (~1 mM) and inhibition by high Ca2+ concentrations (~1 mM). RyR2 and RyR3, however, require substantially higher Ca2+ concentrations for feedback inhibition” Go to annotation (Lanner, 2012, p. 220)
“The action potential in the t-tubules activates voltage sensitive dihydropyridine receptors (DHPRs), also known as L-type Ca2+ channels (Cav1.1), located in the t-tubular wall. The DHPR are in close physical contact with the RyR1 in the SR membrane. When activated, DHPR opens RyR1 by mechanical interaction. The free cytoplasmic (myoplasmic) Ca2+ concentration is very low (~50 nM) under resting conditions, whereas [Ca2+] inside SR is high (~1 mM). The low myoplasmic Ca2+ is maintained mainly by the adenosine trisphosphate (ATP) consuming SR Ca2+-ATPase (SERCA) [33, 34]. Following of the action potential, RyR1 opens which results in release of Ca2+ from SR and a transient increase in myoplasmic Ca2+. The myoplasmic Ca2+ binds to troponin C, initiating movement of tropomyosin, which allows actin and myosin interaction, and force development. After the action potential the SR Ca2+ release terminates. SERCA pumps Ca2+ back into SR and myoplasmic Ca2+ returns to resting levels and that stops myosin actin interaction [28, 30, 35]. In cardiac muscle, action potentials are initiated by pace maker cells. The action potential is longer (~200 ms) compared to skeletal muscle (~3 ms) [29, 36]. The longer action potential allows for the DHPRs (Cav1.2) to be open for a sufficient duration to permit Ca2+ influx to occur. Influx of Ca2+ ions induce the opening of the RyR2 and Ca2+ release from SR, a process known as Ca2+-induced Ca2+ release. The increase in myoplasmic Ca2+ enables actin and myosin interaction” Go to annotation (Lanner, 2012, p. 220)
“2+ returns to resting levels by SERCA-mediated pumping of Ca2+ to SR and by extrusion of Ca2+ via the Na+-Ca2+ exchanger (NCX)” Go to annotation (Lanner, 2012, p. 222)
“Several mutations in both RyR1 and RyR2 are associated with human disorders. For example, the first of these to be identified in 1960 was malignant hyperthermia (MH) [37] and later central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular dysplasia (ARVD)” Go to annotation (Lanner, 2012, p. 222)
“in the heart increased phosphorylation is associated with increased SR Ca2+ leak, which contributes to reduced contractile function and increased propensity for arrhythmias [45–49]. In skeletal muscle, increased SR Ca2+ leak is linked to impaired muscle functions and exercise tolerance in mice” Go to annotation (Lanner, 2012, p. 222)
“MH is a potentially life-threatening disorder typically caused by mutations in the RyR1 channel. MH mutations predispose an affected individual to potentially fatal hypermetabolic reactions triggered by anesthetics (e.g. isoflurane and halothane), depolarizing muscle relaxants (e.g. succinylcholine) and exertion and heat challenge” Go to annotation (Lanner, 2012, p. 223)
“RyR1 is considered to be the major molecular target for dantrolene [73, 75, 76] and direct or indirect binding of dantrolene to RyR1 is believed to decrease SR Ca2+ release and thereby halt the MH episode [73]. However, adverse side-effects of dantrolene e.g. drowsiness, hepatoxicity, and significant muscle weakness preclude it from prophylactic usage” Go to annotation (Lanner, 2012, p. 224)
“mutations in RyR1 are associated with the rare congenital myopathy CCD and the related multiminicore disease and nemaline myopathy [77–79]. CCD exhibits autosomal dominant and recessive models of inheritance [79]. CCD is believed to be the most common congenital myopathy and the total incidence of congenital myopathies is estimated to be around 6/100,000 live births [77]. Many patients with CCD also test positive for MH susceptibility in the characteristic in vitro caffeine contracture test (IVCT). Thus, they should be considered at risk of developing malignant hyperthermia episodes during general anesthesia [80]. Common clinical features of CCD in humans include muscle atrophy, lower limb skeletal muscle weakness leading to delayed motor developmental, and skeletal deformities e.g. scoliosis.” Go to annotation (Lanner, 2012, p. 224)
“CPVT was first described in the 1970s as a familial tachyarrhythmia disorder induced by exercise and emotional stress leading to sudden death in individuals with structurally normal hearts” Go to annotation (Lanner, 2012, p. 225)
“As it is recognized that b-adrenergic stimulation triggers ventricular tachycardia in CPVT, b-blockers are the considered first-line therapy today, but unfortunately they are not completely effective in preventing life-threatening arrhythmias” Go to annotation (Lanner, 2012, p. 225)
“Recent reports show that flecainide treatment completely prevents adrenergicinduced arrhythmias in a mouse model of CPVT and in humans with CSQ2 and RyR2 mutations [95–97]. Flecainide is an approved antiarrhythmic drug known to block sodium channels but has showed remarkable efficacy in preventing spontaneous SR Ca2+ release by inhibiting RyR2 opening [96]. Lidocaine is another Na+ blocker that does not inhibit RyR2 and has very low clinical effect on CPVT” Go to annotation (Lanner, 2012, p. 226)
“ARVD is also a rare inherited disorder caused by RyR2 mutation located in same regions as CPVT and homologous with RyR1 mutations in MH and CCD” Go to annotation (Lanner, 2012, p. 226)
“ARVD patients also exhibit exercise- and adrenergic-induced fatal arrhythmias [99, 101]. Therapeutic options for ARVD remain limited, antiarrhythmic drug therapy e.g. b-blockers has been used but is not completely effective in preventing life-threatening arrhythmias [102]. Today implantable cardioverter/defibrillator appears to be the best treatment; it is an invasive method which is a risk itself, but has shown to be successful in averting sudden cardiac death” Go to annotation (Lanner, 2012, p. 226)