The ryanodine receptor leak how a tattered recept

Authors: Thomas H Fischer Lars S Maier Samuel Sossalla

Publish Date: 2012/08/30

Volume: 18, Issue: 4, Pages: 475-483

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Abstract

It has been persuasively shown in the last two decades that the development of heart failure is closely linked to distinct alterations in Ca2+ cycling A crucial point in this respect is an increased spontaneous release of Ca2+ out of the sarcoplasmic reticulum during diastole via ryanodine receptors type 2 RyR2 The consequence is a compromised sarcoplasmic reticulum Ca2+ storage capacity which impairs systolic contractility and possibly diastolic cardiac function due to Ca2+ overload Additionally leaky RyR2 are more and more regarded to potently induce proarrhythmic triggers Elimination of spontaneously released Ca2+ via RyR2 in diastole can cause a transient sarcolemmal inward current and hence delayed after depolarisations as substrate for cardiac arrhythmias In this article the pathological role and consequences of the SR Ca2+leak and its regulation are reviewed with a main focus on protein kinase A and Ca2+calmodulindependent kinase II We summarise clinical consequences of “leaky RyR2” as well as possible therapeutic strategies in order to correct RyR2 dysfunction and discuss the significance of the available dataHeart failure is characterised by a progressive deterioration of cardiac function and represents a major public health burden Despite a number of wellestablished therapies the prevalence as well as the mortality of heart failure are still alarmingly high Heart failure remains the most frequent reason for hospital admission of patients older than 65 years 1 In the USA the number of hospitalisations due to heart failure has more than tripled between 1979 and 2004 2 The overall prevalence of heart failure is estimated to be about 2  3 More than 10  of people older than 80 years are affected many of them are highly limited as to their physical capacities and thus do suffer significantly in everyday life Furthermore the prognosis of heart failure patients is still miserable There are estimated survival rates of only 50  5 years and 10  10 years after diagnosis 4 5 6Huge efforts have been made to further elucidate underlying pathomechanisms and identify new targets for innovative therapies The aetiologies of heart failure are various stretching from coronary artery disease and heart valve dysfunctions to toxic influences on the myocardium or infectious diseases Arterial hypertension could be identified as the most frequent risk factor in this context 7 The common final path is an impairment of myocardial function Importantly systolic as well as diastolic function can be compromised independently leading to similar clinical manifestations Current definitions of heart failure have taken this into account by distinguishing between heart failure with preserved ejection fraction HFpEF and heart failure with reduced ejection fraction HFrEF According to the guidelines of the American Heart Association HFpEF is defined by symptomatic heart failure and a left ventricular ejection fraction of at least 50  8 This entity has gained increasing attention in recent years as up to 50  of heart failure patients can indeed be classified there 1 9 and evidencebased medical therapy is still lackingOn a histological and cellular level heart failure could be linked to several alterations including fibrosis inflammation and apoptosis Furthermore it has become more and more obvious that a fully functional excitation–contraction coupling process in the cardiomyocyte is fundamental for both a normal systolic and diastolic functionMechanisms of excitation–contraction coupling in cardiomyocytes arrows indicate Ca2+ shifts in systole left and diastole right Ltype Ltype Ca2+ channel RyR2 ryanodine receptor type 2 SR sarcoplasmic reticulum PLB phospholamban TnI troponin I NCX Na+–Ca2+exchanger SERCA2a sarcoplasmic endoplasmic reticulum Ca2+ATPase 2a P phosphateDuring phase 0 of an action potential fast Na+influx leads to a steep increase of the membrane potential increasing the probability that the voltage dependent Ltype Ca2+ channels will open Thereupon Ca2+ions passively drawn by a concentration and electrochemical gradient enter the cytoplasm and maintain the plateau phase of the action potential Inside the cell they bind to ryanodine receptors type 2 RyR2 that are located on the surface of the SR and trigger the release of an even bigger amount of Ca2+ out of the SR This mechanism of Ca2+induced Ca2+ release leads to a prominent increase in cytosolic Ca2+ that binds to troponin C TnC and thereby induces actin–myosin interaction In diastole Ca2+ has to be eliminated from the cytosol to allow relaxation of the myofilaments This is mainly achieved by an active energyconsuming Ca2+reuptake into the SR via the sarcoplasmic reticulum Ca2+ATPase type 2a SERCA2a A smaller amount of Ca2+ is extruded out of the cell via the Na+/Ca2+exchanger NCX which is a facilitated diffusion in which the electrochemical potential gradients of Na+ and Ca2+ are the source of energy to drive the transport NCX in its “forward” mode produces an electrical current because 3 Na+ are exchanged for 1 Ca2+ In human cardiomyocytes the reuptake of Ca2+ into the SR makes up for approximately 70  of the systolic Ca2+ depending on the heart rate 10 Around 28  are pumped out of the cell via NCX The remaining 2  are allotted to Ca2+ uptake into mitochondria and elimination via Ca2+ATPases in the plasma membrane 11As the cyclic alterations of cytosolic Ca2+ concentrations make up the molecular trigger for cardiac contraction and relaxation it is a matter of course that this system is elaborately regulated and highly adaptable to physical demands SERCA2a activity is influenced by phospholamban PLB that is one of the major mediators of the cardiac contractility response upon βadrenergic stimulation 12 Inhibition of SERCA2a by PLB is dependent on the phosphorylation status of PLB and is most pronounced when PLB is unphosphorylated Protein kinase A PKA as well as the Ca2+/calmodulindependent protein kinase IIδ CaMKIIδ is able to phosphorylate PLB at specific residues serine 16 and threonine 17 respectively and thereby abandon its inhibitory effect on SERCA2a A second subcellular microdomain is the RyR2complex that consists of several proteins and whose Ca2+ release capacity and diastolic closure can be regulated via phosphorylation by PKA and CaMKII 13 14 15 16 17 18 19 at Ser2809 and Ser2815 respectively Furthermore protein phosphatases 1 and 2a were found to regulate the phosphorylation status of several Ca2+ handling proteins 20Deteriorations of excitation–contraction coupling in heart failure arrows indicate Ca2+ shifts in systole left and diastole right diastolic Ca2+ leak is highlighted in red changes in protein function and ion concentrations are indicated by vertical red arrows ↑ increase ↓ decrease Ltype Ltype Ca2+ channel RyR2 ryanodine receptor type 2 SR sarcoplasmic reticulum PLB phospholamban TnI troponin I NCX Na+–Ca2+exchanger SERCA2a sarcoplasmic endoplasmic reticulum Ca2+ATPase 2a P phosphate

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