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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(I Ca,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.Â
Excitation-contraction coupling (ECC) is the process in which anÿaction potentialÿtriggers a myocyte to contract. In most excitable cells, the response of muscle fibres to excitation signal by rapid depolarization cause physiological response triggering muscle contraction.muscleÂ . Calcium is the ubiquitous second messenger, important electrical activity and can stimulate the myofilaments directly and causing contraction ofÂ 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 duringÿphase 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
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 slow ly 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 ). D uring development and hypertrophy ,T - type calcium current is more prominent and t he T-type current is typically small or absent in ventricular myocytes . The entering of Ca2+ into the cell by passing thorugh I Ca, T is only responsible for smaller amount of Ca2+ than that passing through I Ca, 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 fibre. (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.
In heart muscle cell, the upstr o ke 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).
[Ca2+]i and Ca2+ sparks
Both [Ca2+]I and [Ca2+]Tot determine the development of contraction which produces both isometric force and rapid shortening. ( Moss, 2001) The strength of cardiac contraction can be changed by two ways: (1) by changing the amplitude or duration of the Ca2+ transient, and (2) by changing the myofilament sensitivity to Ca2+. The sensitivity of myofilament calcium is increased by contracting the myofilament when the heart fills with blood leading to stronger contraction. Caffeine and certain inotropic agents can enhance the myofilament sensitivity whereas, the increased concentrations of phosphate and Mg2+ ( 3 of which occur in myocardial ischemia) and acidosis. Beta-adrenergic activation can also reduce myofilament Ca2+ sensitivity.
Ca2+ sparks is the process of spontaneous release of Ca from SR which was first described by using confocal fluorescence microscopy. Cheng et al.(Cheng et al.,1993). The release of SR Ca via RyR Channels or Single L-type Ca channel openings generates Ca sparks. [220,230](8). Spark probability may be depend on binding of two Ca2+ ions to the RyR.(Lopez-Lopez et al.,1995;Santana et al.,1996). Thus, local cytosolic[Ca]i is important in sparks frequency and SR Ca release.
Role of Sarcoplamic Recticulum
The amount and fraction of Ca2+ release which depends on the level of SR Ca2+ load can release for a given ICa trigger (Shannon et al.,2000). More RyR Sensitivity to [Ca2+]i at high load of [Ca2+]SR leads to increase spontaneous SR Ca2+ release. Decrease in SR Ca2+ release( which is induced by ICa ) can be due to low SR[Ca2+] content. The lower the SrCa2+ release, the more Ca2+ influx through Na+/Ca2+ exchange. Low concentration in SR Ca2+ may contribute to turn-off Ca2+ release from SR during E-C coupling. SR Ca2+ concentration can be increased by more Ca2+ influx, decreasing Ca2+ efflux or increasing Ca2+ uptake into SR. Phospholamban, an endogenous inhibitor of SR Ca2+ ATPase, is relieved by activation of cAMP-dependent or Calmodulin-dependent Protein kinase. When this phospholamben becomes phosphorylated, Ca2+ uptake by SR is increased and allow faster twitch relaxation and decline of [Ca2+]i. Targeted knockout of phospholamben leads to hyperdynamics hearts with negative consequence.(Brittsan & Kranias,2000).
Regulation of Calcium current
Ica can be variable physiologically and pharmacologically. During physiological sympathetic stimulation of heart, Catecholamines stimulate b-adrenegic receptors, which improve contraction (inotropy) and relaxation ( lusitorpy) and [Ca2+] decline. In addition, stimulation of b-adrenergic receptor stimulate a GTP-binding protein which accelerate Adenylyl cyclase for the cAMP production. cAMP activates PKA, which phospharylates severe protein such as Phospholamban, RyR, L-types Ca2+ channels, troponin I and myocin binding protein C ( which are related to excitation- contraction coupling). Phosphorylation of Phospholamban and troponin I activate reuptake of SR Ca2+ and dissociation of Ca2+ from the myofilament and develop to relaxation ( Lusitropic effect). The inotrophic effect of PKA activation is mediated by the combination of increased Ica and greater availability of SR Ca2+. The pharmacological effects f L-type Ca channels is in which calcium sensitivity to dihydropyridines,( nephedipine, amlodipine, nitrendine, nimodipine, nisoldipine). Most of the DHPs inhibit Ica and they are called Ca-channel blockers. In DHPs, there are two other types of specific L-type Ca channel blockers (A) phenyalkylamines such as verapamil, D600) and (B) benzothiazepines (eg, diltiazem), and these agent can interact directly with the Ca channel (Glossmann et al.,1985). Verapamil can block the calcium channel in the open state but it require depolarization pulse) and this is called use dependent. The neutral ligands ( nitrendipine and nisoldipine) can block Ica whether the calcium channel was either in the opening state or inactivated state which is in steady depolarization, and does not require depolarization pulse) as they are voltage dependent than use dependent.
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.Â
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 I N a/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) .Â
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).Â
Ca influx via IP3 pathway
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+ fromÂ SR via IP3 receptors which is located on the SR.Â 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 enter into the cell is slow and there is the lowering of the cytosolic calcium concentration because calcium is taken back by the SR and removing of calcium from the troponin C and finally initial sarcomere length is restored.Â For relaxation and cardiac ventricular filling, 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 (Puglisi et al.,1996).Â SR Ca2 + uptake can be prevented by either thapsigargin orÂ 10mmol/L of caffeine, complete removal of extracellular Na + and Ca2+ can prevent sodium calcium exchange ,
Either carboxyeosin or elevated [Ca2+ ] I inhibit sarcolemmal Ca2 + -ATPase ,Â and mitochondrial Ca2 + uptake can be inhibited by rapid dissipation of the electrochemical driving force for SR Ca2 + uptake by using the protonophore FCCP. In rabbit ventricular myocytes, 70%of the activator Ca2 + removed by the SRCa2 + -ATPase from the cytosol, whereas 28%was removed by NCX, onlyÂ '1% for the sarcolemmal Ca2 + -ATPase and mitochondrialÂ Ca 2+ uniporter remove 1% of calcium from SR ( the last two pathways are calledÂ slow systems). The SR Ca2 + -ATPase activity is higherÂ in rat ventricular myocytes due to more pump molecules in unit cell volume ( Hove-Madsen & Bers,1993). Ca2+ removal through Na+/Ca2+ exchange is lower,Â 92% with SR Ca2+ATPase, 7% with NCX,Â the slow system with 1% respectively. In mouse ventricle, the uptake mechanism is quite similar to rat, (Li et al.,1998)Â whereas the balance of Ca2 + fluxes in human ventricle myocytes, guinea pig, ferret, are more similar to rabbit myocytes.(Pieske,et al.,1999).Â
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-fe e dback 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 R yanodine 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 & Bers,1997 ). 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 r y anodine 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 h igher [ Ca2+ ] I ( Valdivia et al.,1995). RyRs i nactivation may be important i n reducing inappropriate SR Ca2+ release events between ea ch heart beats.Â In summary Ca2+ release during excitation-contraction coupling is terminated mainly by a local RyRs inactivation and partialÂ SR luminal Ca2+ depletion which lead to reduce RyR opening s and variant of stochastic attrition also contributes.
Role of calcium channels in cardiac hypertrophy and heart failureÂ
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 intracellular 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 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, there is decreasing in binding sites in rat hearts,(Dixon,1990). Whereas there is no changes in human heart depending on the extent of the disease process. The release of SR Ca depend on a single channel property of the L-type Ca2+ channel. Therefore, the single channel properties of the L-typeCa2+ channel can be altered in hypertrophy, causing the abnormalities in contraction. This is supported by the observation that L-type Ca2+ current in all animal models of cardiac hypertrophy and failure (Xiao,1994) although there is no increase duration was observed in ventricular myocytes from humans with heart failure (Beuckelmann,1991) .Ca2+ can enter the cell through pathways and ion channels and transporters, that may lead to altered E-C coupling with the development of disease. Increases in T-type Ca2+ current have also been observed in hypertrophied cells due to growth hormone secreting tumors (Xu,1990). There have been no data related with the role of the Na+/Ca2+ exchanger or ICa TTX in E-C coupling from hypertrophied or heart failure.
In normal excitation-contraction coupling, calcium influx through the LTCC plays an important role and abnormal calcium handling has recently been reported in heart disease (Bers,2002). So, LTCC becomes significant for implications of therapy in treatment of LVH by treating with calcium channel blockers,which has been reported in animal models ( Feron et al,1996). In clinical practice, calcium channel blockers reduce blood pressure and causing regression of LVH, but has not been significant for prolonged survival. In the formation of LVH, signals regulated by calcium play in a significant role.(Hill ,2000). If calcium-regulated signaling pathways are inhibited, LVH due to pressure overload can be diminished without interfering the systole. A partial reduction of LTCCexpression that is sufficient to prevent the activation of calcium regulated signaling pathways and prevent the development of LVH, without impairing normal excitation contraction coupling. Regulation of the LTCC expression has become a significant treatment for LVH and other cardiac diseases associated with calcium abnormalities such as hypertrophic obstructive cardiomyopathy(HOCM). HOCM isÂ treated with calcium channel blockers, surgical treatment in some of the cases ,and also by nonsurgical septal reduction techniques (Chang et al.,2003) but have adverse effects such as inflammation, fibrosis as well as arrhythmogenesis. Focally regulated LTCC by a vector which can reduce gene expression is also the alternative treatment forÂ Â HOCM.Â Â 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.