In cardiac muscle, exitation-contraction coupling is mediated by the calcium induced calcium released from sarcoplasmic recticulum via ryanodine receptor through L-type calcium channels. Although Ca2+ induced Ca2+ released by L-typed calcium current is the primary pathway for triggering Ca2+ from sarcoplasmics, there are many mechanism for activation of Ca2 + release from sarcoplasmics reticulum such as CICR mediated by T-typed calcium current, CICR triggered by calcium influx through Na+/Ca2+ exchange, and CICR triggered by calcium through tetrodotoxin(TTX)-sensitive Ca2+ current(ICa,TTX). As calcium is a important second messenger which is essential in cardiac electrical activity and also a main activator of the myofilament which causing contraction, mishandling of calcium will will lead to many pathophysiological conditions.
Excitation-contraction coupling (ECC) is the process in which anÂ action potentialÂ triggers a myocyte to contract. In most excitable cells,Â muscle fibers respond to the excitation signal with a rapid depolarization which is coupled with its physiological response and causing contraction. Calcium s the ubiquitous second messenger which is essential in cardiac electrical activity and is the direct activator of the myofilaments, which cause contraction of heart.( Bers,2001). In mammalian cardiac myocytes, the process of excitation-contraction (E-C) coupling is mediated by Ca2+influx from the extracellular space triggering Ca2+ Calcium- induced Calcium release (CICR) from the sarcoplasmic reticulum (SR) (Bers, 1991; Stern & Lakatta, 1992). When action potential reach the myocyte, it undergoes depolarization and calcium ions enter the cell duringÂ phase 2 which gives rise to the plateau phase of action potential through L type calcium channel which is located on the sarcolemma and then trigger the calcium release from the sarcoplasmic recticulum. Intracellular calcium concentration and calcium influx trigger the contraction of heart due to the binding of Ca2+ to cardiac muscle fiber protein, troponin C. For activation of SR calcium release, CICR is the widely most accepted mechanism by L-typed calcium current, SR calcium release can be triggered by calcium influx through sodium-calcium exchange, through tetrodotoxin-sensitive Ca2+urrent,or Inositol (1,4,5)-triphosphate. Declining of calcium level in the cells cause the detachment of calcium from myofilament and resulting the relaxation of heart. There arefour main pathways for Ca2+ transport out of the cytosol including SR Ca2+ ATPase, sarcolemmal Na+/Ca2+ exchange, sarcolemmal Ca2+-ATPase or mitochondrial Ca2+ uniport. Scince CICR is a positive-feedback mechanism, its have to be terminated which is essential for diastolic refilling of the heart. There are three main pathways for termaination of calcium release such as local depletion of SR Ca2+, RyR inactivation (or adaptation), and stochastic attrition. (Lukyanenko et al.,1998). The improper contractile function and abnormal heart rate is due to the mishandling of calcium in heart muscle
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cell . (Pogwizd et al.,2001).
Calcium handling in contraction of heart
Ca2+ is essential for the body mechanisms. In cardiac muscle, calcium have a role for the ability to make the cardiac cell to contract. L-type calcium channels and T-type calcium channels are two major types of calcium channels in the cells of cardiac tisues. (Bean,1989). At more positive membrane potential (Em), L-type (Ica) can activates and inactivates and slowly inactivated and is sensitive to dihydropyridines.(Tsien et al.,1987). On the other hand, T-type (Ica) cause the activation and inactivation at increasing negative membrane potential (Em) and dihydropyridines cannot block effectively.(Nowycky et al.,1985). During development and hypertrophy,T -type calcium current is more prominent and the T-type current is typically small or absent in ventricular myocytes. The entering of Ca2+ into
the cell by passing thorugh ICa,T is only responsible for smaller amount of Ca2+ than that passing through ICa,L. In most ventricular myocytes. L-type calcium current is almost negligible. It shows
that the releasing and refilling is mainly provided by Ica,L but it is not take part in pacemaking very much. The relative amounts of ICa,L and I Ca,T vary among Cardiac myocytes. L-type calcium current and T-type calcium current is variable among cardiac myocytes. T-types calcium current is present in all cardiac myocytes whereas L-type calcium current is have larger component in the canine Purkinje ï¬ber. (Zhou,1998). Depolarization of action potential causes activation of calcium current. During an action potential, the amount of calcium entry is limited by calcium dependent inactivation at the cytosloic side.
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In heart muscle cell, the upstroke of action potential is due to the entering of Na+ ions via voltage gated Na+ channels and it is called fast inward current. The immediate repolarization is not possible due to inactivation of Na+ channel rapidly and initial depolarization allow the entering of calcium through voltage-grated Ca2+ channels and it is called second inward current. The rate of sodium channels inactivation is more rapid than that of calcium channels and so that the entering of Ca2+ into the cell provide the membrane potential to close to 0mV for some part of action potential of heart muscle.(Reuter,1984).
Calcium induced calcium release during E-C coupling
There have been demonstrated that Calcium induce SR calcium release in skinned ventrilcular myocytes. (Fabiato and Fabiato,1975). There are evidence that main mode of E-C coupling in cardiac myocytes is by Ca influx via L-type Ca channels and can triggers SR Ca release. (Bers,1991). When calcium channel becomes deactivates, before calcium channels close, calcium transient is induced by a large and short-lived ICa and causing contraction. Moreover, Ca channel activation without Ca influx also could not induce SR calcium release.( Nabauer et al.,1989). When there is a high concentration of Ca buffer in the cell, ICa activate SR Ca release channel.(Adachi-Akahane et al.,1996). Ca2+ release from SR is most commonly activated by L-type Ca2+ channels, this mechanism is called Ca2+ induced Ca2+ release (CICR). There have been little doubt that E-C coupling occurs physiologically but there are other mechanism which can coexit and give rise to the function effects.
Ca influx via ICa,T
In ventricular myocytes, T-type calcium current is relatively small or absent but more prominent during development and hypertrophy. Because of T-type calcium current is typically small and inactivates very rapidly ,the total amount of Ca influx via T-type calcium current is probably small compared to that via ICa,L .(Zhou,1998). Moreover, T-type calcium current is negligible in most of ventricular myocytes. So,ICa,T only plays a minor role in triggering SR Ca release during action potential.
Ca influx via Na+/Ca2+ exchange
Resarch made in guinea pig ventricular myocytes show that T-type Ca2+ current can also trigger Ca2+ release from SR, but it is not as efficient as L-type (Sipido,1998). Since T-type calcium channel is non-functional in most of the myocytes of ventricle, it does not play a major role for exitation-contraction coupling although it may function like Ica,L. Release of Ca2+ from SR in response to Ca2+ influx through L-type Ca2+ channels is the most common pathway, but other mechanism of Ca2+ release from SR by Na+/Ca2+ exchanger in condition of Ca2+ overload is also shown ( Berlin et al,1987; Bers et al.,1988). The result of Ca2+ release by Na+/Ca2+ exchanger has been proved by examination on rats ( Wasserstorm and Vites,1996 ), rabbit ( Litwin et al., 1998 ) and guinea pig ( Sipida et al.,1997 ). There are two ways of triggering Ca2+ release from SR by Na+/ Ca2+ exchanger. First mechanism is Na+ current by increasing local [Na+]sm, increasing Ca2+ entry through Na+/Ca2+ exchanger and causing SR Ca2+ release (Levesque et al.,1994). Second one is depolarization directly stimulate outward INa/Ca and Ca2+ release and contraction when L-type Ca2+ channel become blocked or at high positive Em (Levi et al.,1994;LItwin et al.,1998). Increased intracellular sodium stimulate the Na+/Ca+ exchanger (Evans and Cannell, 1997 ) and, if INa is low, the reverse current of the Na+/Ca2+ exchange for Ca2+ release by SR become unlikely. Therefore, INa or medication that alters the intracellular sodium become the regulator of calcium release from sarcoplasmic reticulum. Stimulation via hormone, such as activation of ET-1 receptor ( Alvarez et al., 1999) , and increasing frequency of action potential (Simor et al., 1997). increases INa so that triggering Ca2+ release from SR is slower via Ca2+ influx through Na+/Ca2+ exchanger than through L-type calcium channel (Spido et al.,1997).
Ca influx via TTX sensitive-Na channels
Aggarwa et al.,1997 reported that calcium entry via tetrodotoxin-sentive Na channels.TTX-sensitive Na channels can also mediates calcium induced calcium release. It can alter selectivity of cardiac Na channels triggeres by either activation of b-adrenergic agonist or cardioactive steroids or cardiac gycosides, making Na channel prefer Ca2+ than Na channels and it is called altered selectivity mode or slipe mode. The tetrodotoxin-sensitive Ca influx could trigger the SR Ca2+ release. This effects could be mediated by increased Ica and SR Ca-pump activity or by Na+/K+ ATPase inhibition and reduced Ca efflux via Na+/Ca2+ exchange for glycosides.( Borgatta et al.,1991).
Ca influx via IP3 pathway
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Inositol (1,4,5)-triphosphate can trigger Ca2+ release from SR and endoplamic reticulum in many cell types, by means of IP3 receptors. In ventricular myocytes, (primarily isoform 2).( Lipp et al.,2000). Activation of IP3 signal transduction pathway can trigger the release of Ca2+ from SR through IP3 receptors located on the SR. Although high concerntration of InP3 can cause Ca2+ release in cardiac myocytes, the rate and extent of Ca2+ release are very much lower than CICR.. Moreover, action potential cannot stimulate the InP3 production.( Kentish et al.,1990). The production of InP3 contractile force is increased by cardiac alpha-adrenergic and muscarinic agonists.( Poggioli et al.,1986). InP3 only has a minor modulatory role in cardiac excitation-contraction coupling.
In summary, cardiac SR calcium release is mainly through CICR by L-type calcium current, Ica is the dominant Ca2+source .Other mechanism that mentioned above show minor role in SR calcium release .
At the end of phase 2, calcium entry into the cell slows and calcium is taken back by the SR resulting in lowering of the cytosolic calcium concentration and removing of calcium from the troponin C and finally initial sarcomere length is restored. For relaxation and ventricular filling to occur, the Ca2+ must be removed from the cytosol to lower [Ca2+]i, allow the relaxation. Ca2+ have to dissociate from troponin C but require Ca2+ transport out of the cytosol by four pathways involing SR Ca2+-ATPase, sarcolemmal Na+/Ca2+ exchange, sarcolemmal Ca2+-ATPase or mitochondrial Ca2+ uniport. There are selective inhibition for each transporter during cardiac myocyte relaxation and [Ca2+]i decline.12-15(7). SR Ca2+ uptake was prevented by either thapsigargin or 10mmol/L caffeine, NCX was prevented by complete removal of extracellular Na+ and Ca2+, sarcolemmal Ca2+-ATPase was inhibited by either carboxyeosin or elevated [Ca2+]i, and mitochondrial Ca2+ uptake was blocked by rapid dissipation of the electrochemical driving force for Ca2+ uptake using the protonophore FCCP. In rabbit ventricular myocytes, the SRCa2+-ATPase removes 70%of the activator Ca2+ from the cytosol, whereas the NCX removes 28%,with only '1% each for the sarcolemmal Ca2+-ATPase and mitochondrial Ca2+uniporter (which are called the slow systems). In rat ventricle, the SR Ca2+-ATPase activity is higher due to more pump molecules in unit cell volume (Hove-Madsen & Bers,1993). Ca2+ removal through Na+/Ca2+ exchange is lower, 92% for SR Ca2+ATPase, 7% for NCX, 1% for the slow system. In mouse ventricle, the uptake mechanism is quite similar to rat, (Li et al.,1998) whereas the balance of Ca2+ fluxes in guinea pig, ferret, and human ventricle are more similar to rabbit.(Pieske,et al.,1999).
In contraction and relaxation of myocyte, the amount of calcium removed from the cell during relaxation must be the same as the amount of calcium entry for contraction in each beat, if not the cell may gain or lose calcium.
Termination of calcium release
Ca2+induced Ca2+release is a positive-feedback mechanism but turning off of the calcium is essential for diastolic refilling of the heart. Three major wayfs or termination of calcium release include local SR depletion, RyR inactivation (or adaptation) and stochastic attriction. (Sham et al.,1998;Lukyanenko & Gyorke,1998). Stochastic attriction mean L-type Ca2+ channels and all Ryanodine receptors are closed simultaneously, then local [Ca2+]i will fall drop rapidly to the sub-threshold level and distrubing the release from SR. But this is only used for 1DHPR and 1-2 RyRs but for other numbers of channels, they all will not close at once. In addition, local depletion of SR Ca2+ also may terminate SR Ca2+ but it cannot completely turn-off of release, because very long lasting Ca2+ sparks are found that will not decline with time (Satoh & Bersï¼Œ1997). But there are other region of SR can also limit local SR Ca2+ depletion. During a gobal Ca2+ transient, the whole (Ca2+)SR declines. [Ca2+]SR depletion might lead to the turning-off global SR Ca2+ release during a relaxation. There are two types of RyR inactivation both of which depend on [Ca2+]i One is absorbing inactivation (like in Na+ channels), in which the ryanodine receptor is cannot reopening until it recovers.( Sham et al.,1998;Lukyanenko & Gyorke,1998). The another one is called adaptation in which ryanodine after activation leads to a lower open probability, but can be reactivated by higher [Ca2+]I (Valdivia et al.,1995). RyRs inactivation may be important in reducing inappropriate SR Ca2+ release events between each heart beats.
In summary Ca2+ release during excitation-contraction coupling is terminated mainly by a local RyRs inactivation and partial
SR luminal Ca2+ depletion which lead to reduce RyR openings and variant of stochastic attrition also contributes.
Role of calcium channels in cardiac hypertrophy and heart failure
Cardiac hypertrophy is the main important leading cause of cardiac morbidity and mortality in cardiovascular system. It is associated with heart failure in the absence of a myocardial infarction. Cardiac hypertrophy is associated with significant changes in myocardial contraction. These contractile dysfunctions are followed by changing in the whole-cell intracellur calcium transient. The pathogensis of cardiac hypertrophy and heart failure related with the role of Ca2+ channels remains controversial. L-type Ca2+ current concentration is remain the same in rats myocytes with hypertrophy due to aortic banding.( Scamps et al.,1990), cats with pulmonary artery banding.(Kleinman,1988) cardiomyopathy in Syrian hamsters,( Sen,1994) ,and ventricular myocytes in human from patients with heart failure,( Beuckelmann et al.,1992). In contrast, L-type Ca2+ channel concentration is increased in hypertrophic myocytes from guinea pigs with banding of aorta,( Ryder,1993) , and banding of renal artery in rats, ( Keung,1989),while it decreased in ventricular cells from cats with aortic banding ,( Nuss,1993). To further confuse the issue, the effects of cardiac hypertrophy on L-type Ca2+ currents seems to depend on the duration of the disease. There is also an increased in dihydropyridine binding sites in the myocardium of hamsters with hereditary cardiomyopathy. Then, decrease in binding sites in rat hearts,(Dixon,1990). No changes in human heart depending on the extent of the disease process. The release of Ca from the SR seems to depend on a single channel property of the L-type Ca2+ channel that is not reflected in the magnitude of the current i.e.,the mean open time, single channel current,etc. Therefore, the single channel properties of the L-typeCa2+ channel could be altered in hypertrophy, causing the abnormalities in contraction noted. This possibility is supported by the observation that L-type Ca2+ current is prolonged in myocytes from virtually all animal models of cardiac hypertrophy and failure (Xiao,1994) although no increase in duration was observed in ventricular myocytes from humans with heart failure (Beuckelmann,1991) Ca2+ can enter the cell through other ion channels and transporters, which may account for the altered E-Ccoupling with the development of disease. Increases in T-type Ca2+ current have also been reported in hypertrophied cells due to growth hormone secreting tumors (Xu,1990). There is no data concerning the role of the Na/Ca2+ exchanger or ICa TTX in E-C coupling Ca from hypertrophied or failing cardiac myocytes.
In normal excitation-contraction coupling, there are important role of calcium influx through the LTCC and the significance of calcium mishandling in heart disease, have recently been reported. (Bers,2002). Importance of the LTCC as a therapeutic target for left ventricular hypertrophy has been confirmed in many animal models that demonstrate reduction in hypertrophy by calcium channel blockers. ( Feron et al,1996). Clinically, calcium channel antagonists reduce blood pressure and causing regression of LVH, but it is not used for prolongation for survival. Calcium regulated signaling also plays a central role in the development of LVH.(Hill ,2000). The inhibition of calcium-regulated signaling pathways has been shown to reduce pressure overload-induced LVH without disturbing systolic function. A partial reduction of LTCC expression that is sufficient to prevent the activation of calcium regulated signaling pathways and prevent the development of LVH, without impairing normal excitation contraction coupling. Modulating the expression of LTCC may represent a specific therapy for LVH and other cardiac iseases associated with calcium mishandling for example, hypertrophic obstructive cardiomyopathy (HOCM), is conventionally treated with pharmacological calcium channel blockers but in selected cases treated by surgical, and most recently Chang et al.,2003 found that nonsurgical septal reduction techniques as a means of ameliorating LV outflow obstruction.but have side effects,including inflammation, fibrosis, and arrhythmogenesis. Focal modulation of LTCC by a vector capable of chronically suppressing gene expression may represent an attractive
alternative therapy in HOCM. LTCC as a potentially novel
therapeutic target for calcium mishandling with associated diverse cardiac disease. The role of RNA interference in modulating the expression of LTCC, regulating calcium influx and preventing LVH.