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Cardiac Excitation–Contraction Coupling

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Cardiac Excitation–Contraction Coupling insight review articles Cardiac excitation–contraction coupling Donald M. Bers Department of Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, Illinois 60153, USA (e-mail: [email protected]) Of the ions involved in the intricate workings of the heart, calcium is considered perhaps the most important. It is crucial to the very process that enables the chambers of the heart to contract and relax, a process called excitation–contraction coupling. It is important to understand in quantitative detail exactly how calcium is moved around the various organelles of the myocyte in order to bring about excitation–contraction coupling if we are to understand the basic physiology of heart function. Furthermore, spatial microdomains within the cell are important in localizing the molecular players that orchestrate cardiac function. ardiac excitation–contraction coupling is the Ca2+ transport out of the cytosol by four pathways involving process from electrical excitation of the SR Ca2+-ATPase, sarcolemmal Na+/Ca2+ exchange, sar- myocyte to contraction of the heart (which colemmal Ca2+-ATPase or mitochondrial Ca2+ uniport. propels blood out). The ubiquitous second Here I discuss the key Ca2+ transport systems in cardiac messenger Ca2+ is essential in cardiac electrical myocytes, how they interact dynamically and how they Cactivity and is the direct activator of the myofilaments, are regulated. The increasingly important area of local which cause contraction1. Myocyte mishandling of Ca2+ is a molecular signalling in microdomains will also be addressed. central cause of both contractile dysfunction and arrhythmias in pathophysiological conditions2. The role of calcium in contraction and flux balance During the cardiac action potential, Ca2+ enters the cell Although Ca2+ is the switch that activates the myofilaments through depolarization-activated Ca2+ channels as inward (the end effectors of excitation–contraction coupling), con- 2+ 2+ Ca current (ICa), which contributes to the action potential traction is graded and depends on [Ca ]i and other factors. plateau (Fig. 1). Ca2+ entry triggers Ca2+ release from the Figure 2a shows the amount of total cytosolic [Ca2+] 2+ 2+ 4 2+ 2+ sarcoplasmic reticulum (SR). The combination of Ca ([Ca ]To t [Ca ]i plus bound Ca ) that must be supplied to influx and release raises the free intracellular Ca2+ concen- and removed from the cytosol during each cardiac beat. 2+ 2+ tration ([Ca ]i), allowing Ca to bind to the myofilament Half-maximal activation of contraction requires roughly 2+ 2+ protein troponin C, which then switches on the contractile 70 µmol of Ca per litre of cytosol, which would raise [Ca ]i 2+ 2+ machinery. For relaxation to occur [Ca ]i must decline, to 600 nM. This ratio of bound:free Ca indicates that there is allowing Ca2+ to dissociate from troponin. This requires powerful cytosolic Ca2+ buffering (~100:1)1. Figure 1 Ca2+ transport in ventricular myocytes. Inset 3Na 2K shows the time course of an 2+ action potential, Ca Sarcolemma ATP NCX ATP transient and contraction measured in a rabbit ventricular myocyte at 37 7C. Ca 3Na NCX, Na+/Ca2+ exchange; Ca Ca ATP, ATPase; PLB, RyR I PLB Ca SR ATP phospholamban; SR, Ca Ca sarcoplasmic reticulum. Ca 2Na Ca H Myofilaments H Ca Na Ca [Ca]i NCX AP 3Na (Em) T-tubule Contraction 200 ms 198 © 2002 Macmillan Magazines Ltd NATURE | VOL 415 | 10 JANUARY 2002 | www.nature.com insight review articles 2+ The development of contraction force depends on [Ca ]i and [Ca2+] in highly nonlinear relations, as a result of strong To t a myofilament cooperativity with respect to [Ca2+] (refs 1,3,4). i 100 Moreover, the physiological contraction generates both isometric force (or ventricular pressure) and rapid shortening (to eject blood). 80 There are two main ways to change the strength of cardiac 100 2+ 60 contraction: by altering the amplitude or duration of the Ca tran- K1 = 600 nM 2+ / 2 sient, and by altering the sensitivity of the myofilaments to Ca . 50 n=4 Myofilament Ca2+ sensitivity is enhanced dynamically by stretching 40 Force the myofilaments (as the heart fills with blood), resulting in a 20 0 stronger contraction. This is due, in part, to the transverse filament (% of maximum) Force 0 500 1,000 1,500 2,000 Free [Ca]i [nM] lattice compression that occurs on stretch, which enhances the 0 actin–myosin interaction5. This lateral compression is an important 0 30 60 90 120 150 Added ∆[Ca] (µmol l-1 cytosol) autoregulatory mechanism by which the heart adjusts to altered total diastolic filling (the classic Frank–Starling response). Myofilament Ca2+ sensitivity is reduced by acidosis, and by b Rabbit elevated phosphate and Mg2+ concentrations (all three of which 75 100% occur during ischaemia). Myofilament Ca2+ sensitivity is also Total reduced by b-adrenergic activation (see below), but enhanced by 2+ 50 70% caffeine and certain inotropic drugs. The rapid kinetics of the Ca SR transient prevent the myofilaments from fully equilibrating with 2+ [Ca ]i during a normal twitch (especially in the rising phase). Thus, 2+ 25 although contractile strength is indicative of underlying Ca tran- NCX 28% sients, there is a dynamic interplay between Ca2+ and myofilaments cytosol) -1 Slow (SL Ca-ATPase & Mito) during excitation–contraction coupling. 2% Ca2+ must be removed from the cytosol to lower [Ca2+] and allow 0 i mol l 0.0 0.5 1.0 1.5 2.0 relaxation. This is achieved by several routes, the quantitative impor- µ tance of which varies between species (ref. 6; and Fig. 2b). In rabbit 75 Rat 100% 2+ ventricular myocytes, the SR Ca -ATPase pump removes 70% of the Ca flux ( 92% Total activator Ca2+, and Na+/Ca2+ exchange removes 28%, leaving only 2+ about 1% each to be removed by the sarcolemmal Ca -ATPase and 50 SR mitochondrial Ca2+ uniporter (the last two are collectively referred to as ‘the slow systems’). The amount of Ca2+ that leaves the cytosol by entering mitochondria is inconsequential with respect to 25 excitation–contraction coupling, but slow cumulative changes in Slow intra-mitochondrial [Ca2+] can stimulate key dehydrogenases that NCX 7% increase the production of NADH (nicotinamide adenine dinu- 0 1% 0.0 0.2 0.4 0.6 0.8 1.0 cleotide) and ATP to match increased energetic demands7. Time (s) The activity of SR Ca2+-ATPase is higher in rat ventricle than in rabbit ventricle (because of a greater concentration of pump molecules)8, and Ca2+ removal through Na+/Ca2+ exchange is lower, Figure 2 Quantitative Ca2+ fluxes during excitation–contraction coupling. a, Amount resulting in a balance of 92% for SR Ca2+-ATPase, 7% for Na+/Ca2+ of Ca2+ required for contractile activation, assuming a diastolic intracellular Ca2+ 2+ 2+ exchange and 1% for the slow systems (Fig. 2b). Analysis in mouse concentration ([Ca ]i) of 150 nM and cytosolic Ca buffers including troponin C ventricle is quantitatively like rat9, whereas the balance of Ca2+ fluxes (Ca2+ and Ca2+/Mg2+ sites), myosin, SR Ca2+-ATPase, calmodulin, ATP, creatine 1 2+ in ferret, dog, cat, guinea-pig and human ventricle are more like phosphate and sarcolemmal sites . Inset shows force as a function of [Ca ]i (that is, 1 & 2+ 4 2+ rabbit . Thus, mouse and rat ventricle (which also show very spike- force is equal to 100/(1 {600/[Ca ]i} ); ref. 1). b, Integrated Ca fluxes during 2+ like action potentials) poorly mimic human with respect to the twitch relaxation in rabbit and rat ventricular myocytes. Curves are based on [Ca ]i 2+ 2+ quantitative balance of cellular Ca flux. Moreover, during heart and the [Ca ]i dependence of transport rates measured for each system. failure in humans and rabbits, functional expression of SR Percentages are relative contributions to Ca2+ removal4. SL, sarcolemmal; Ca2+-ATPase is reduced and Na+/Ca2+ exchange is increased10, such SR, SR Ca2+-ATPase; Mito, mitochondrial Ca2+ uniporter. 2+ that these systems contribute more equally to the decline in [Ca ]i (refs 1,2). These changes counterbalance each other with respect to 2+ 2+ –1 –1 twitch relaxation and [Ca ]i decline, leaving it unaltered. But both drives Ca into resting myocytes (at ~1 µmol l cytosol s ) by 2+ 2+ 12 changes tend to reduce Ca content in the SR, limiting SR Ca unknown pathways . As T-type ICa is negligible in most release, and this may be a central cause of systolic contractile deficit in ventricular myocytes, ICa generally refers to the L-type here. ICa is heart failure. activated by depolarization, but Ca2+-dependent inactivation at The amount of Ca2+ extruded from the cell during twitch the cytosolic side limits the amount of Ca2+ entry during the relaxation must be the same as the amount of Ca2+ entry for each beat, action potential. This Ca2+-dependent inactivation is a local effect otherwise the cell would gain or lose Ca2+ (and would not be in steady and is mediated by calmodulin bound to the carboxy terminus of the state). Indeed, complementary measurements of Ca2+ influx and SR Ca2+ channel13,14. Ca2+ release during a twitch confirm this expectation in rabbit and L-type Ca2+ channels (dihydropyridine receptors; DHPRs) are rat1,11. This provides a quantitative framework of dynamic Ca2+ fluxes located primarily at sarcolemmal–SR junctions where the SR Ca2+ in ventricular myocytes. release channels (or ryanodine receptors; RyRs) exist15. During exci- tation–contraction coupling, SR Ca2+ release also contributes to 2+ 2+ Calcium current Ca -dependent inactivation of ICa (refs 16,17). Indeed, the total Ca 2+ 2+ Myocytes exhibit two classes of voltage-dependent Ca channels influx through ICa is reduced by about 50% when SR Ca release (L- and T-type)1 and the large electrochemical [Ca2+] gradient also occurs (from 12 to 6 µmol Ca2+ l–1 cytosol)18.
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