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Abstract: Calcium (Ca), a universal intracellular second messenger, plays as a role in contractile activation function in cardiac muscle. Ca activates cardiac myocytes to form contraction during action potential (AP) and need 100µmol/L of Ca from cytosol and there are a number of Ca channels and transporters in order to carry the Ca in and out of the myocytes.
Calcium is a ubiquitous intracellular second messenger, involved in many functions e.g., electrophysiology, excitation-contraction (E-C) coupling, contraction itself, energy consumption, cell death by apoptosis, transcriptional regulation. The action potential causes contraction of the cell by a process known as E-C coupling. The transient increase of (Ca)i is caused by Ca induced Ca release (CICR) from the sarcoplasmic reticulum (SR) which store major intracellular calcium. This Ca-dependent process work in orchestrated symphony in order to produce contractile function of the heart. Ca-dependent regulation works through specific Ca-binding proteins e.g. CaM and troponin C (TnC). Action potential elicited by field stimulation induced transient intracellular Ca concentration that was highly inhomogeneous.
Ca which enters from ICA activates SR Ca release through RyR causing the activation of contraction. And relaxation is caused by the extrusion of Ca via NCX and SR Ca uptake via the SERCA. Calcium calmodulin dependent protein kinase (CaMKII) can phosphorylate phospholambn (PLB), leading to enhanced Ca uptake from SR. RyR also phosphorylate by CaMKII leading to spontaneous diastolic SR Ca release. That release of Ca activates inward current of NCX and arrhythmogenic delayed afterdepolarization (DADs). Ca and Na channel subunits are phosphorylated by CaMKII and leading to alteration Ica and Ina gating, thereby prolong the APD and increase the propensity for early afterdepolarizations (EADs). While calmodulin (CAM) modulate RyR, Ica, and Ina gating, CaMKII also modulate Ito. Adenylate cyclise (AC) is activated by β-adrenergic receptors (β-AR) leading to production of cyclic AMP (cAMP) and activate PKA. PKA phosphorylates SR Ca uptake, ICA, IKs, and RyR resulting in increase in net Ca transient amplitude. This lead to activation of CaM and CaMKII, but β-AR can activate CaMKII via Ca-independent pathway may be present.
There are 10-25 L-type Ca channels and 100-200 RyRs are clustered between sarcolemma and SR constitutes a local Ca signalling complex called couplon. Local [Ca]i rises in the junctional cleft to 10-20uM in less than a millisecond, and activates SR RyR Ca release. Even opening of a single Ca channel can cause Ca release but during AP, to create a safety and effective coupling, several Ca channels need to open. There are about 6-20 RyRs open in one couplon, on estimation of SR Ca release and single-channel current. This release, which is synchronized by local CICR among RyRs raises cleft [Ca]i to 200-400 µM. Then Ca diffuses to the cytosol to activate myofilaments from the cleft. In normal, Ca release from one couplon can't activate the neighbouring junction because [Ca]i declines over that distance (Ca is diluted in larger volume). To become synchronous contractile activation of couplons, all 20,000 couplons must be simultaneously activated leading to AP and activation of Ca current Ica.
RyR is more sensitive to [Ca]i when SR Ca content is elevated. The higher the Ca content the increase in RyR sensitivity contribute to Ca to calsequestrin bindings, which binds to triadin and RyR inside the SR in a Ca-sensitive manner. Although ICA,L is the main trigger of E-C coupling, sodium calcium exchange (NCX) can also modulate E-C coupling in 3 ways. First, rises in submembrane [Na]i by INA which drive influx of Ca through NCX leading to triggering of ICA. Secondly, when a Ca channel opens, the entry of Ca via NCX will normally reverse because of high local Ca. Third, Ca entry via NCX may raises cleft [Ca]i until SR Ca release is triggered.
PKA and CaMKII can phosphorylate and regulate SR Ca uptake (via phospholamban phosphorylation), ICA and RyR. These kinases phosphorylate different sites on these proteins by each process. PKA and CaMKII are sitmulated by sympathetic activation and function synergistically. B-adreneargiv agonists activate CaMKII effecs on RyR independently of PKA or Ca, and when PKA losses efficacy, CaMKII mediates long-term inotropic effect of β-adrenergic. So CamKII is considered to be downstream of PKA and elevated Ca transients.
Ca transient is contributed by Ca influx and SR Ca release and removal of Ca from cytosol is by SR Ca-ATPase (SERCA) and sarcolemmal extrusion. In normal conditions, the amount of Ca by SR must be the same with the amount released, and the amount that enters ICA and NCX must be same to the amount extruded. For Ca extrusion NCX is crucial and there is no other ca extrusion mechanism in myocytes. Myocytes can reduce ICA,L leading to shortening of the APD resulting in decreasing in ca influx.
Myofilaments are activated by Ca influx and CICR from the SR. Increase in [Ca]i lead to binding of Ca to troponin C (TnC) to activate contraction. After binding, TnC binds troponin I (TnI) more strongly and pull TnI off its actin-binding site. That troponin/ tropomyosin complex rolls deeper into the groove of the actin filament leading to interaction of myosin head with actin. That attachment of myosin head to actin leads to formation of crossbridge, which can push the troponin/ tropomyosin complex even deeper into the groove and facilitate crossbridges formation in neighbouring TnC sites. This contributes the cooperativity of myofilaments in Ca sensitivity curves. The affinity of Ca to bind to TnC is enhanced by crossbridge binding and force generation leading to slow in Ca dissociation and prolong the active state.
In myofilaments, Ca dissociates rapidly and the myofilaments that are independent of Ca process fully dictate relaxation kinetic and maintain maximal systolic pressure due to Ca-free crossbridge cycling is long-lived. The rate of [Ca]i decline accelerate relaxation, but PKA-dependent TnI phosphorylaition has weaker relaxation effect and binding of Ca to TnC influence relaxation under isometric conditions. So relaxation is influenced by TnC Ca affinity, [Ca]i decline and intrinsic crossbridge and there is a dynamic interplay between Ca binding, crossbridge cooperativity and myofilament deactivation.
The Frank-Starling law, the greater the diastolic filling leads to the stronger contraction, explain by anatomy of sarcomere. As the length of sarcomere increase, there is overlapping of thick and thin filaments that overlapping allows more crossbridges to form and the development of stronger force. And as the SL increase to the optimum overlap, the cardiac muscles become very stiff. Ca sensitivity dramatically increase as the increase in SL because as the length of myocyte and sarcomere increase, the width and filament lattice spacing decrease leading to increase likelihood of crossbridge formation and cooperative Ca binding. As increasing SL, the osmotic compression of the myofilament lattice can mimic the enhanced myofilament Ca sensitivity. As the length of SL increase, myofilament Ca sensitivity is enhanced dominantly by lattice spacing. Ca uniporter transport Ca into the mitochondria where as Ca extrusion is by Na/Ca antiporter (NCX) and this mitochondrial NCX is differ from sarcolemmal NCX in that transport 1 Ca into the mitochondria and extrude 2 or 3 Na outside of the mitochondria. And Na can also be extruded by electroneural Na/H exchange NHX and the remaining protons are extruded to the cytosol by electron transport chain which includes the cytochromes. Dehydrogenases that supply reducing equivalents is activated by increase in amount of mitochondrial Ca leading to synthesis of ATP.
Through the channels and exchangers, Ca carries and regulates ionic current, leading to AP configuration, arrhythmogenesis and cell-cell communication. There are two types of membrane potential (Em) dependent Ca current Ica in cardiac myocytes, L-type (ICa,L) and T-type (ICA,T) which contribute to pacemaker activity, the AP upstroke and plateau phases and arrhythmias. ICA,T activates at negative Em than ICa,L IcaL but inactivates more quickly and by Ca influx independent. ICA,T whichi s expressed mainly in conducting and pacemaker cells in the heart is not present in most ventricular myocytes. ICA,T is activated early in diastole and contribute to diastolic depolarization. ICa,L is recruited and contribute to depolarization as depolarization proceeds, and drives the upstroke of the regenerative AP in pacemaker cells. As Ca entry through L-type Ca channel increases there is a larger trigger for Ca release from the SR resulting in the larger systolic Ca transients. [Ca]i from previous beat activate inward Na/Ca exchange current (INCX) during early diastolic depolarization . Ca is released from the SR in during diastole via RyRs which is triggered by ICA,T or ear ICa,L or spontaneously by a SR Ca release clock. Ca from previous heart beat refill SR and the RyR recovers from refractoriness, the high luminal SR [Ca] causes local SR Ca release during diastolic depolarization. Transsarcolemmal current is not produced by SR Ca release itself, but a second window of inward INCX is activated by local rise in [Ca]i that contributes to late diastolic depolarization. ICa,L does not contribute to the rapid rising phase of the AP in ventricular myocytes. ICa,L is quickly activated by Ina-dependent rapid depolarization; the amplitude of ICa,L is not maximal near the AP peak because ICa,L activation is time dependent. After AP peak, there is Ina inactivation and transient outward K currents owed by an early repolarisation phase. This causes increase ICa driving force. So a rapid rise in conductance and an increase in driving force are activated by ICa. This is value in synchronizing SR Ca release during E-C coupling that synchronization is critical for optimal contractility, but ICa is influenced by Ca release during the early AP. Voltage-dependent and Ca-dependent inactivation mediate ICa,L turn off during the AP, but Ca-dependent is more predominant. CaM also mediates Ca-dependent inactivation of IcaL. When the amount to local [Ca]i near the inner channel mouth increases leading to ICa and /or SR Ca release, Ca binds to the CaM. This causes Ca-CaM to bind to the α1c near the apoCaM-binding site, leads to accelerating inactivation. Ca-dependent inactivation was caused by Ca binding to the low-affinity animo end of prebound Cam, but carboxy end is important for Ca- dependent ICa facilitation. Cardiac myocytes also show Ca-dependent ICa facilitation, which depends on Ca_CaM-dependent protein kinase. If facilitation of ICa happens for a longer timescale that results in a moderate increase in Ica amplitude and slow the inactivation. CaMKII can associate directly with the Ca channel and phosphoryltes on the both α1c and β2 subunit have been implicated in mediating ICa facilitation. To limit Ca influx under conditions in which Ca influx of SR Ca release is high, Ca-dependent Ica inactivation may function as a feedback system, and this become a protection against cellular Ca overload, which can lead to arrhythmias and cell death. The amount of entry of Ca via ICa is varies among cell types and species in AP and with AP configuration and SR Ca release.
ICa,L amplitude and shift activation are increased by β-adrenergic agonist to more negative Em. This is occur through a local signalling complex in which adenylate cyclise, cAMP , PKA and β-adrenergic receptors are all right at the channel. In under dynamic control by local [Ca]i and Em, Ica contributes to inward current.
The Ca transporter in the heart is the Na/Ca exchange (NCX) which takes responsibility for extruding the Ca that enters through ICa. That NCX transporter is electrogenic, extruding 1 Ca with 3 Na inward so one net change and carries ionic current INCX. Em and the amount of Na and Ca on both sides of the membrane controlled INCX which is reversible transporter. Low [Ca]i limits the absolute rate of Ca extrusion and diastolic inward of INCX, at rest Em is negative to ENCX and Ca extrusinon is favoured thermodynamically. During AP, Em passes ENCX favouring the Ca influx and outward INCX. But this is a short-lived because when ICa,L is activated leading to SR Ca release, so local [Ca]i is very high near the membrane and drive ENCX back above Em causing inward of ICX and extrudes Ca again. The greater inward current is formed by the higher Ca trasiendt which leads to further repolarisation. So in normal state, INCX is an inward current throughout most of the AP and it is driven by [Ca]i and tempered by the positive Em during AP. Ca entry and outward INCX can continue even though ICa does not occur in some cell region. INCX is inactivated at high [Na]i like those Em-dependent ion channels and this is most prominent at high [Na]i. But cellular Ca overload may be prevented by this inactivation of INCX at hight [Na]i level. Our mammalian NCX does not work without [Ca]i even with the Ca influx direction. In order to prevent [Ca]i from decreasing too low, Ca efflux mechanism will be turned off and when cellular [Ca]i is high, Ca efflux to become more active to avoid overload of Ca. Phosphatidylinositol biphosphate (PIP2) and ATP also regulate NCX but this state is only important in heart's pathological conditions. PKA stimulate and PKC active NCX.
There are many Ca-regulated currents that take part in cardiac electrophysiology. Ca-activated Cl current (ICL(Ca)) contributes a transient outward current early during the AP when local submembrane [Ca]i is high and Em is very positive to ECl. And there are also Ca-activated cation-nonselective current in cardiac myocytes. Connexons, gap junction channels, which connects all myocytes in the heart electrically, are inhibited by prolong increase in [Ca]i and CaM and local signalling of Ca may be involved. In potentially dying myocytes in severe Ca overload can isolate themselves from the rest of the heart, by avoiding the depolarizing and Ca0overloading influences on neighbouring cells.
Elevated [Ca]i increase the slowly activating delayed rectifier K current (IKs) and the Ca senor channel protein KCNQ1 is bind to CaM. Ca modulates INA through CaM directly by CaMKII-dependent phosphorylation of the SNC5A channel forming unit. CaMKII associate and phosphorylates the Na channel and alters the INA gating. CaMKII makes INA availability to more negative membrane potential and leading to increase the accumulation of channels in intermediate inactivation and recover from inactivation slowly. Increase in heart rate leads to loss-of-function effect that reduce the INA. CaMKII also modulates the cardiac Ito and causing Ito inactivation slowly. Shortening of APD was enhanced by these effects. So numerous ion channels are modulated by Ca and cause complex electrophysiological effects. DADs, EADs or increased automaticity can result arrhythmias and these are the part of Ca signalling or transport. Spontaneous SR Ca release result from high SR Ca levels causes DADs takes off from the resting Em after AP polarization. Release of Ca from SR causes an aftercontraction and a transient inward current that depolarizes Em toward threshold for an AP.
Inositol 1,4,5 triphosphate (InsP3) can induce Ca release from G protein-coupled receptors, then which also activate the neighbouring RyR. Those InsP3 are found profusely and coexist with RyR in atrial myocytes but their numbers are low in ventricular myocytes.
There are a lot of factors that responsible for initiating and controlling the amplitude of the systolic Ca transient in cardiac myocytes. During AP the release of Ca from intracellular is required for SR. And a negative feedback mechanism is needed to Ca control in SR and for the amplitude of systolic Ca transient. The changes in amount of Ca into the cell result in inotropic responses which don't need to change in the amount of SR Ca.