how do calcium ions produce contraction of heart

How do calcium ions produce contraction of heart? The calcium that enters the heart cell through the calcium ion channel activates the ryanodine receptor to release enough calcium from the sarcoplasmic reticulum

to initiate heart muscle contraction. This is done by binding to another structure, named troponin, inside the heart muscle cell.

Full Answer

How do calcium ions affect the heart?

Effect of Calcium Ions. An excess of calcium ions causes effects almost exactly opposite to those of potassium ions, causing the heart to go toward spastic contraction.

What is the role of calcium in cardiac muscle contraction?

(ICa,TTX). As calcium is an important second messenger which is essential in regulating cardiac electrical activity as well as being the main activator of the myofilaments to which cause cardiac contraction. Mishandling of calcium is thought to lead many pathophysiological conditions.

What triggers calcium-induced calcium release from cardiac myocytes?

In mammalian cardiac myocytes, the process of ECC is mediated by Ca2+ influx from the extracellular space that triggers Ca2+ Calcium – induced Calcium release (CICR) from the sarcoplasmic reticulum (SR) (Bers, 1991; Stern & Lakatta, 1992).

What type of calcium channels enter the cardiac cell during action potential?

Thus, the L-type Ca2+ channels are the majority of calcium channels responsible for entering of Ca2+ into the cardiac cell during phase 2 (plateau phase) of the action potential.

What is the function of calcium ions in cardiac muscle?

In the cells of the cardiac muscle, calcium ions play a crucial role in coupling excitation and contraction. It is thus one of the most important second messengers since it regulates calcium-dependent cell signaling and in turn essential cell functions.

What ions cause the heart to contract?

Subsequent activation of L-type Ca2+ channels produces a small influx of Ca2+ into the cell (ICaL), which triggers a much larger Ca2+-induced Ca2+ release from the SR through the cardiac RyRs, thus initiating contraction, as the released Ca2+ binds to the myofilaments.

How does calcium initiate contraction?

In striated muscle, calcium causes a shift in the position of the troponin complex on actin filaments, which exposes myosin-binding sites (Fig. 2A). Myosin bound by ADP and inorganic phosphate (Pi) can then form cross-bridges with actin, and the release of ADP and Pi produces the power stroke that drives contraction.

Why is calcium needed for muscle contraction?

Calcium triggers contraction by reaction with regulatory proteins that in the absence of calcium prevent interaction of actin and myosin.

How does calcium-induced calcium release work?

What is calcium-induced calcium release? This is the process — commonly known by the acronym CICR — whereby calcium promotes its own release from intracellular calcium stores. The diffusion of calcium within cells is greatly retarded by buffers.

How do calcium ions and ATP contribute to muscle contraction and relaxation?

Ca++ ions are pumped back into the SR, which causes the tropomyosin to reshield the binding sites on the actin strands. A muscle may also stop contracting when it runs out of ATP and becomes fatigued. The release of calcium ions initiates muscle contractions.

What is the role of calcium ions in muscle contraction quizlet?

What is the role of calcium ions in the contraction of skeletal muscle? The release of calcium ions triggers the immediate regeneration of creatine phosphate to power the contraction. Calcium ions bind to the troponin-tropomyosin complex and remove their inhibitory action on actin/myosin interaction.

How is muscle contraction initiated?

1. A Muscle Contraction Is Triggered When an Action Potential Travels Along the Nerves to the Muscles. Muscle contraction begins when the nervous system generates a signal. The signal, an impulse called an action potential, travels through a type of nerve cell called a motor neuron.

Why is calcium important in cardiac muscle?

In the cells of the cardiac muscle, calcium ions play a crucial role in coupling excitation and contraction. It is thus one of the most important second messengers since it regulates calcium-dependent cell signaling and in turn essential cell functions.

What is the coupling of calcium channels in cardiac muscle cells?

Excitation-contraction coupling occurs within cardiac muscle cells in response to calcium-induced calcium release, CICR. When L-type calcium channels that are voltage-gated are activated by the depolarization of the myocyte membrane, they allow calcium ions from outside the cell to sweep into the cytoplasm.

What causes calcium to rise in the cell?

CICR causes the concentration of calcium inside the cell to rise rapidly but for a very brief time. This leads to the beginning of contraction by the binding of calcium in the cytosol with calcium-sensitive myofilaments like actin, myosin and troponin.

What enzyme releases calcium ions from the sarcolemmal reticulum?

When calcium ions are released by these myofilaments, and pumped back into the sarcoplasmic reticulum through the SR calcium ATPase (SERCA2a) enzyme , and finally expelled from the myocyte through the sarcolemmal sodium/calcium exchanger (NCX), the muscle relaxes to cause diastole of the heart muscle.

What are the two proteins that control calcium current density?

Both protein kinases and phosphatases act on LTCC complexes as well, controlling their activity levels, and this results in more precise regulation of calcium current density as well as the activation of calcium signaling.

What is the role of reactive oxygen species in cardiac signaling?

We now know that reactive oxygen species (ROS) like superoxide anion (O 2-) or hydrogen peroxide (H 2 O 2) are critical regulators of the process of cardiac signaling via calcium ions. The modifications of components of the cardiac myocytes that contribute to calcium signaling that depend upon ROS are present in almost all these cells.

What is calcium induced calcium release?

As originally described, calcium-induced calcium release is a positive feedback system in which one might expect the Ca released from the SR to trigger further release of Ca until the SR is empty. This contrasts with the observation that Ca release is graded with the amplitude of the L-type Ca current94,95and, indeed, the SR only releases ≈50% of its Ca during the Ca transient.96The resolution of this paradox came from both modeling97and experimental work showing that, under normal conditions, Ca release from one release site of the SR remains localized and does not activate other release sites. In other words Ca release is controlled locally. Under resting conditions, localized releases of Ca from individual clusters of RyRs are seen as Ca sparks.98Depolarization of the surface membrane activates more and more L-type Ca channels resulting in an increasing number of sparks until spatially uniform Ca release is observed.99

How does Ca regulate cardiac contraction?

Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca2+]i). Normal function requires that [Ca2+]ibe sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca2+]i.

How does caffeine affect the RyR?

A striking example is provided by considering the effects of changing the open probability of the RyR. Adding submillimolar concentrations of caffeine potentiates the opening of the RyR (without affecting Ca2+entry via ICa), increasing the amplitude of the systolic Ca transient. After a few beats, however, the amplitude of the Ca transient in caffeine is identical to that in control56,57(Figure ​(Figure3A).3A). The explanation of this result is that potentiation of RyR opening initially increases the amplitude of the Ca transient making efflux greater than influx so the cell is no longer in a steady state. The SR therefore loses Ca, decreasing the amplitude of the Ca transient until a new steady state (influx=efflux) is reached, with a decreased SR Ca content offsetting the potentiation of the RyR produced by caffeine. This occurs when the amplitude of the Ca transient returns to the control (pre-caffeine) level (Figure ​(Figure3B).3B). The underlying decrease of SR Ca, responsible for the decline of the Ca transient amplitude to the control level, has been measured directly using a fluorescent indicator in the SR58(Figure ​(Figure33A).

What changes occur in dyadic structure in heart failure with a reduction in the number of t-?

Major changes occur in dyadic structure in heart failure with a reduction in the number of t-tubules in the ventricle27and, in the atrium, the loss of virtually all.18T-tubule loss and the consequent loss of tight coupling between L-type Ca2+channels and RyRs result in the so-called orphaned RyRs and a reduction in the synchronicity and amplitude of the Ca2+transient.28,29

What is the cardiac dyad?

The cardiac dyad is a specialized signaling nexus concerned primarily with the initiation of cardiac contraction. Classically, it consists of clusters of L-type Ca2+channels on the sarcolemma closely apposed (≈15 nm) across the dyadic cleft to clusters of RyRs on the SR membrane. In addition to these basic requirements for excitation–contraction coupling, the cardiac dyad may also be considered as containing additional structures that may contribute to or modulate Ca2+release from the SR during systole (Figure ​(Figure1).1). Of these, the most extensively studied is NCX that has been argued via its reverse-mode action to contribute to Ca2+influx early during the action potential.20However, assuming dyadic and cytosolic intracellular Na+are similar during diastole (5–10 mmol/L,21) such reverse-mode NCX is thermodynamically limited leading to the suggestion that Na+entry via voltage-gated Na+channels (INa) may raise dyadic Na+sufficiently early during the action potential to facilitate effective reverse-mode NCX. Indeed, Leblanc and Hulme22first demonstrated the modulating effect of INaon Ca2+release from the SR. Subsequent experiments suggested that a subpopulation of neuronal Na+channels are localized to the t-tubule and thence dyadic environ23–25; however, Brette et al26also concluded that although neuronal Na+channels were concentrated on the t-tubule, they were not required for cardiac excitation–contraction coupling.

What happens if Ca transporters across intracellular membranes such as SR or mitochondria are affected?

What happens if Ca transporters across intracellular membranes such as SR or mitochondria are affected? The simple answer is that if the Ca influx into the cell is unchanged, then the Ca efflux must be unaffected. This either means that the amplitude and kinetics of the systolic Ca transient are unaffected or that a change of amplitude is exactly compensated by one of time course such that efflux is unaffected (see below for consideration of mitochondrial function).

Does Ca cycling take notice of flux balance?

Work on Ca cycling often takes insufficient notice of the flux balance condition. As discussed below, it is essential that postulated mechanisms and explanations are tested to ensure that they are compatible with the requirement for Ca efflux to equal influx such that steady state conditions can prevail.

What is the role of calcium in the heart?

Calcium plays important roles in the electrical activity and pumping function of the heart. Calcium particles enter the heart muscle cells during each heartbeat and contribute to the electrical signal that coordinates the heart's function.

Where is calcium stored in the heart?

In heart muscle cells, most of the calcium is stored inside a chamber named the sarcoplasmic reticulum. The calcium in the sarcoplasmic reticulum is released during heart muscle contraction and transported back inside the sarcoplasmic reticulum during relaxation. Red arrows indicate the movement/flow of calcium from one place to another.

Where is calcium stored in the heart muscle cell?

During relaxation, calcium has to be detached from troponin and expelled out of the cell or stored back inside the sarcoplasmic reticulum. Figure 2 - A heart muscle cell and its components.

What is the charge of calcium particles?

Calcium particles, which have an electrical charge, enter the heart muscle cells during each beat and contribute to the electrical signal. In addition, these calcium particles initiate contraction by binding to specialized machinery within the cell.

What is the role of calcium particles in electrical activity?

Research during the last decades has revealed that calcium particles are responsible for the link between electrical activation and mechanical contraction. The squeezing together of heart muscle cells, which makes the heart pump blood. ( Figure 1 ).

What is the cause of heart rhythm disorders?

In some diseases, the doors controlling the movement of calcium malfunction, leading to abnormal electrical signals, which may cause a group of heart diseases called heart rhythm disorders. In addition, abnormal regulation of calcium may directly impair pumping function or relaxation of the heart.

Which chamber stores calcium?

In addition to the supply of calcium from outside the cell, there is a big chamber inside the cell, named the sarcoplasmic reticulum, that stores most of the calcium required for heart contraction. The sarcoplasmic reticulum chamber also has entrance and exit doors for calcium.

What are the roles of calcium channels in cardiac muscle?

In cardiac muscle, calcium has a role for the ability to make the cardiac cell to contract. There are five types of calcium channels; L, T, N, P/Q and R types. Among them, L-type and T-type calcium channels are two major types of calcium channels in the cells of cardiac tissues (Bean, 1989). L-type Ca2+ channels have many subunits in the heart such as α1, α2, δ and β subunits. The α1 subunit is the dihydropyridine (DHP) receptors which are important for calcium entry into the cells (Liu et al., 2000). L-type calcium channels (long-lasting) can activates at more positive membrane potential (Em), at greater than -40mV and generate peak inward current at 0mV and slowly inactivated, and is sensitive to dihydropyridines (Tsien et al., 1987). Thus, the L-type Ca2+ channels are the majority of calcium channels responsible for entering of Ca2+ into the cardiac cell during phase 2 (plateau phase) of the action potential. On the other hand, T-type (tiny or transient) Ca2+ channels cause the activation and inactivation at more negative membrane potential (Em) and dihydropyridines cannot block effectively (Nowycky et al., 1985). However T-type Ca2+ channels have faster kinetics than compared to L-type Ca2+ channels. 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 through I Ca,T is only responsible for smaller amount of Ca2+ than that passing through ICa,L. In most ventricular myocytes, T-type calcium current is almost negligible. It shows that the releasing and refilling is mainly provided by Ica,L. The amount of L-type calcium current and T-type calcium current is variable among cardiac myocytes. L-types calcium current is present in all cardiac myocytes whereas T-type calcium current have larger component in the canine Purkinje fiber (Zhou, 1998). Depolarization during the action potential causes activation of calcium current. During an action potential, the amount of calcium entry is limited by calcium dependent inactivation at the cytosolic side. L-type calcium channel is located at the sarcolemmal-SR junction where ryanodine receptors exist (Scriven et al., 2000). There is a negative feedback effect on Ca2+ influx and SR Ca2+ release during excitation-contraction mechanism. When there is increased Ca2+ influx or release, further release of Ca2+ is turned off.

What happens to calcium during action potential?

During an action potential, calcium entry into the cell is slow at the end of phase 2 and there is 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. For relaxation and cardiac ventricular filling, Ca2+ have be removed from the cytosol to lower [Ca2+]i , causing relaxation. Cardiac relaxation to occur, Ca2+ must be dissociate from troponin C and it requires Ca2+ transport out of the cytosol primarily by four main pathways involving, sarcolemmal Na+/Ca2+ exchange, SR Ca2+-ATPase, 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). SR Ca2+ uptake can be prevented by either thapsigargin or caffeine, complete removal of extracellular Na+ and Ca2+ can prevent sodium calcium exchange. Either carboxyeosin or elevated [Ca2+]i inhibit sarcolemmel Ca2+-ATPase, and mitochondrial Ca2+ uptake can be inhibited by rapid dissipation of the electrochemical driving force for SR Ca2+ uptake by using protonophore FCCP. In rabbit ventricular myocytes, 70% of the activated Ca2+ removed by the SR Ca2+-ATPase from the cytosol, whereas 28% was removed by NCX, only 1% for sarcolemmal Ca2+-ATPase as well as mitochondrial Ca2+ uniporter remove 1% of calcium from SR ( the last two pathways are called slow systems). In rat ventricular myocytes, SR Ca2+-ATPase activity is higher due to more pump molecules in unit cell volume (Hove-Madsen & Bers, 1993). On the other hand, Ca2+ removal via Na+/Ca2+ exchange is lower, 92% with SR Ca2+-ATPase, 7% with NCX, the slow systems with 1 % respectively. In mouse ventricular myocytes, the uptake mechanism is quite similar to rat, (Li et al., 1998) while the mechanisms of Ca2+ fluxes in human ventricular myocytes, guinea pig and ferret are more similar to rabbit myocytes (Pieske et al., 1999). In contraction and relaxation of myocytes, the amount of calcium removed from the cell during relaxation must be the same as the amount of calcium entry during contraction in each heart beat, if not, the cell may gain or lose the calcium. Defects in Ca2+ removal also can cause impair relaxation

What is the effect of ICa on the heart?

Ica can be variable physiologically and pharmacologically. During physiological sympathetic stimulation of heart, catecholamine stimulate beta-adrenegic receptors, which improve the force of contraction (inotropic effects) and relaxation (lusitorpic effects) and declining of [Ca2+]i. In addition, stimulation of β-adrenergic receptor stimulates a GTP-binding protein that accelerates adenylyl cyclase for the cAMP production. cAMP activates PKA, which phospharylates severe protein such as phospholamban, RyR, L-types Ca2+ channels, myocin binding protein C and troponin I ( which are related to ECC). Activation and phosphorylation of L-type Ca2+ channels will cause Ca2+ release from SR causing contraction of the heart. Phosphorylation of troponin I and phospholamban stimulate the reuptake of Ca2+ release from SR and Ca2+ is dissociated from the myofilament and develops to cardiac relaxation (Lusitropic effect). The inotrophic effect of PKA (protein kinase A) activation is triggered by the combination greater availability of SR Ca2+ and increased calcium current. Open probability of RyR channels can also be modulated by protein kinase A. RyRs receptors are hyperphosphorylated in heart failure causing a diastolic leak of SR Ca2+. However, whether PKA-dependent phosphorylation will alter during excitation-contraction or not still remain controversial. Moreover, phosphorylation of L-type Ca2+ channels, phospholamban and troponin I are paralleled with activation of ß1-adrenergic receptors in ventricular myocytes that produce inotrophic and lusitropic effects. On the other hand, ß2-adrenergic receptors activation can give more restricted to the enhancement of ICa (Kushel et al., 1999). cAMP production can also be stimulated by the G-protein-coupled receptors such as prostaglandin E and histamine that will lead to little or no effect of inotropic effects (Vila Petroff et al, 2001). Other receptors will also regulate the signaling pathway. For instance, M2-muscarinic receptors activation can decrease cAMP and activation of PKA thereby decreasing Ca2+ entry and release. In addition, this pathway also enhances repolarization. The pharmacological effects of L-type Ca2+ channels are in which calcium sensitivity to dihydropyridines (nephedipine, amlodipine, nitrendine, nimodipine, nisoldipine). Ica is inhibited by most of DHPs and they are called Ca2+-channel blockers. In DHPs, there are two other types of specific L-type Ca2+ channel blockers (1) phenyalkylamines (eg. verapamil, D600) and (2) benzothiazepines (eg, diltiazem), and those agents can act together directly with the Ca2+ channel (Glossmann et al., 1985). Verapamil can inhibit the calcium channel in the open state but it require depolarization pulse) and this is called use dependent. The neutral ligands such as nitrendipine and nisoldipine inhibit ICa depend on the calcium channel whether they are in the opening state or inactivated state , and does not require depolarization pulse as they are voltage dependent than use dependent.

What is the role of Ca2+ in ECC?

ECC and intracellular Ca2+ homeostasis are primarily regulated by sarcoplasmic recticulum (Bers, 1991). Once stimulation, calcium enters the cell, thereby stimulating the release of larger amount of calcium from SR resulting in activation of contractile protein and contraction of the heart. During cardiac relaxation, Ca2+ is taken up by SR by SR Ca2+ ATPase pump and Na+/Ca2+ exchange pump. The key SR Ca2+ release channel involved in cardiac contraction is RyRs and RyR2 is the cardiac isoform. The amount and fraction of Ca2+ release that depends on the level of SR Ca2+ load can release for a given ICa trigger (Shannon et al., 2000). Sensitivity of RyRs receptor to [Ca2+]i at high load of SR Ca2+ leads to increase spontaneous SR Ca2+ release. On the other hand, decrease in SR Ca2+ release (which is induced by ICa ) can be due to low SR [Ca2+] content. The lower the amount of the SR Ca2+ release, the more amount of Ca2+ enter the cells through Na+/Ca2+ exchange. When there is low concentration in SR Ca2+, Ca2+ release from SR is turned off during E-C coupling. Furthermore, SR Ca2+ content depends on the heart rate and duration of action potential. Ca2+ concentration release from SR can be increased by more mount of Ca2+ enter into the cell, by decreasing Ca2+ efflux or increasing SR Ca2+ uptake. Phospholamben, an endogenous inhibitor of SR Ca2+ ATPase, is triggered by activation of cAMP-dependent or calmodulin-dependent protein kinase. When this phospholamben becomes phosphorylated, Ca2+ uptake by SR is increased and allows faster cardiac relaxation and declining of [Ca2+]i. Targeted knockout of phospholamben leads to hyperdynamic hearts with negative effects (Brittsan & Kranias, 2000). Interestingly, lower SR Ca2+ uptake, reduced SR Ca2+ATPase gene and protein expression were seen in failing human heart (Pieske et al., 1995). On the other hand, there has been demonstrated that increased gene expression of sarcolemmal Na+/Ca2+ exchanger was seen in human failing heart (Reinecke et al., 1996).

How does calcium release from the sarcoplasmic reticulum?

In cardiac muscle, excitation-contraction coupling is mediated by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors that are activated by calcium entry through L-type calcium channels on the sarcolemmal membrane. Although Ca2+ induced Ca2+ release triggered by the L-typed calcium current is the primary pathway for triggering Ca2+ from the sarcoplasmic reticulum, there are many other mechanisms that can also activate Ca2 + release from the sarcoplasmic reticulum such as Calcium induced calcium release (CICR) induced by T-typed calcium current, CICR triggered by calcium influx through Na+/Ca2+ exchange, and CICR mediated by calcium through tetrodotoxin (TTX)-sensitive Ca2+ current

What triggers Ca2+ release from SR?

Inositol (1, 4, 5) – triphosphate could trigger Ca2+ release from SR and endoplamic reticulum in different cell types, they are called IP3 receptors. In ventricular myocytes, the major form of InsP3 is isoform 2 (Lipp et al., 2000). There are more InP3 receptors in atrial cells in ventricular myoctyes. Stimulation of IP3 signal transduction pathway can trigger the release of Ca2+ from SR via IP3 receptors which is located on SR. Even high concentration of InP3 in cardiac myocytes could trigger Ca2+ release from the SR, the extent of Ca2+ release from the SR are so much lower than CICR triggered by LTCC. 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). In addition, InP3 pathway only plays a very little minor role in cardiac EC coupling. To conclude for triggering Ca2+ release from SR, CICR in cardiac contraction is mainly through L-type Ca2+channel.Other mechanisms that mentioned above show minor role in SR calcium release.

How does E-C coupling work in cardiac myocytes?

There was been proved that main pathway of E-C coupling in cardiac myocytes is by Ca entry through L-type Ca2+ channels and triggers SR Ca2+ release (Bers, 1991). When calcium channel becomes deactivates, before calcium channels close, calcium transient is induced by a large and short-lived ICa causing contraction. Moreover, Ca2+ channel activation in the absence of Ca2+ influx also cannot induce calcium release from the SR (Nabauer et al., 1989). There is supported that ICa activate SR Ca2+ release channel when there is a high concentration of Ca2+ buffer in the cell (Adachi-Akahane et al., 1996). Ca2+ release from SR is most commonly activated by L-type Ca2+ channels and this pathway is called Ca2+ induced Ca2+ release (CICR). There has been little doubt that E-C coupling occurs physiologically but there are other mechanisms which can exit in parallel and give rise to the functional effects.

How does calcium activate myofilaments?

In both cardiac and skeletal muscle, the force-generating molecular motors (crossbridges) are turned on by increasing the intracellular free calcium level that regulates the troponin-tropomyosin system. However, calcium activation is a two-way process in the sense ...

How does calcium activate the crossbridge?

In both cardiac and skeletal muscle, the force-generating molecular motors (crossbridges) are turned on by increasing the intracellular free calcium level that regulates the troponin-tropomyosin system. However, calcium activation is a two-way process in the sense that activated crossbridges also affect the troponin-tropomyosin system. Here we review the mechanism of calcium action on myofilament proteins, particularly tropomyosin, that affects both the extent and the rate of force development and hence the contractility of the myocardium. At low myoplasmic Ca2+ concentrations tropomyosin is located at the edge of the thin filament, thereby interfering with the formation of strong actin-myosin linkages (blocked state). An increase in Ca2+ activity causes an azimuthal shift of tropomyosin around the filament (by about 30 degrees), thereby increasing the probability of low-force crossbridge interaction, a process which by cooperative effects induces further tropomyosin movement (by an additional 10 degrees) which results in the open state of the filament characterized by forceful crossbridge interaction. (This mechanism may be analogous to that in ligand-gated ion channels, where ligand binding increases the open probability of the pore.) The extent of activation then depends on the free Ca2+ concentration and on the calcium sensitivity of the thin filament that may be affected by protein phosphorylation, crossbridge attachment, the troponin isoform composition of the filament, and novel calcium-sensitizing drugs that act on the contractile or regulatory proteins and thus increase the force of the heart.

Is calcium activation a two way process?

However, calcium activation is a two-way process in the sense that activated crossbridges also af …. In both cardiac and skeletal muscle, the force-generating molecular motors (crossbridges) are turned on by increasing the intracellular free calcium level that regulates the troponin-tropomyosin system. However, calcium activation is ...

How does Ca regulate cardiac contraction?

Cardiac contractility is regulated by changes in intracellular Ca concentration ( [Ca 2+] i ). Normal function requires that [Ca 2+] i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca 2+] i.

How Is Flux Balance Achieved?

(1) The imbalance of fluxes increases cell and therefore SR Ca. (2) Ca release is a steep function of SR Ca content 51, 52 and therefore the amplitude of the Ca transient increases. (3) Increasing the amplitude of the Ca transient increases Ca efflux and decreases Ca entry into the cell. This is because of a combination of 2 factors 52: (1) Ca efflux on NCX is increased by increasing [Ca 2+] i 53 and (2) increased [Ca 2+] i increases Ca-dependent inactivation of the L-type Ca current. 54 (3) This net loss of Ca from the cell decreases SR Ca. These events continue until Ca influx and efflux are equal. A good example of this mechanism in operation is provided by Figure 2B, which shows what happens when the SR has been emptied by exposure to 10 mmol/L caffeine. When stimulation is recommenced, the Ca transient is small because of the low SR Ca content. Consequently, Ca influx is much larger than efflux and the SR Ca content increases. This leads to an increase in the amplitude of the Ca transient until influx and efflux return to balance.

How does caffeine affect the RyR?

A striking example is provided by considering the effects of changing the open probability of the RyR. Adding submillimolar concentrations of caffeine potentiates the opening of the RyR (without affecting Ca 2+ entry via ICa ), increasing the amplitude of the systolic Ca transient. After a few beats, however, the amplitude of the Ca transient in caffeine is identical to that in control 56, 57 ( Figure 3A ). The explanation of this result is that potentiation of RyR opening initially increases the amplitude of the Ca transient making efflux greater than influx so the cell is no longer in a steady state. The SR therefore loses Ca, decreasing the amplitude of the Ca transient until a new steady state (influx=efflux) is reached, with a decreased SR Ca content offsetting the potentiation of the RyR produced by caffeine. This occurs when the amplitude of the Ca transient returns to the control (pre-caffeine) level ( Figure 3B ). The underlying decrease of SR Ca, responsible for the decline of the Ca transient amplitude to the control level, has been measured directly using a fluorescent indicator in the SR 58 ( Figure 3A ).

What is the cardiac dyad?

The cardiac dyad is a specialized signaling nexus concerned primarily with the initiation of cardiac contraction. Classically, it consists of clusters of L-type Ca 2+ channels on the sarcolemma closely apposed (≈15 nm) across the dyadic cleft to clusters of RyRs on the SR membrane. In addition to these basic requirements for excitation–contraction coupling, the cardiac dyad may also be considered as containing additional structures that may contribute to or modulate Ca 2+ release from the SR during systole ( Figure 1 ). Of these, the most extensively studied is NCX that has been argued via its reverse-mode action to contribute to Ca 2+ influx early during the action potential. 20 However, assuming dyadic and cytosolic intracellular Na + are similar during diastole (5–10 mmol/L, 21) such reverse-mode NCX is thermodynamically limited leading to the suggestion that Na + entry via voltage-gated Na + channels ( INa) may raise dyadic Na + sufficiently early during the action potential to facilitate effective reverse-mode NCX. Indeed, Leblanc and Hulme 22 first demonstrated the modulating effect of INa on Ca 2+ release from the SR. Subsequent experiments suggested that a subpopulation of neuronal Na + channels are localized to the t-tubule and thence dyadic environ 23 – 25; however, Brette et al 26 also concluded that although neuronal Na + channels were concentrated on the t-tubule, they were not required for cardiac excitation–contraction coupling.

How does Ca leak affect the systolic Ca transient?

A major effect of Ca leak is to decrease the Ca content of the SR and thence the amplitude of the Ca transient. In this context, an important issue concerns the properties of the leak. Evidence from the Gyorke group using bilayer studies has found that in heart failure, there is an apparent sensitization of the RyR to activation by luminal Ca. 133 This contrasts with a previous study, suggesting that heart failure locked the RyR in a subconducting state. 126 The difference is significant for the effects of leak on the systolic Ca transient. If the leak results from a mechanism that sensitizes the RyR, then (as for the effects of low concentrations of caffeine mentioned above) the sensitization of the RyR will initially compensate for the decrease of SR Ca content and no effect will be seen on the amplitude of the Ca transient. As the leak increases, the SR Ca content falls to such a low level that even the release of 100% cannot sustain a normal-sized Ca transient and the amplitude of the Ca transient declines 134 and efflux is maintained by prolongation of decay. In contrast, if the leak does not result from sensitization of the RyR, then the amplitude of the Ca transient will decline in parallel with SR content. An analogy is provided by comparing the effects of caffeine (sensitizing-) with those of ryanodine (nonsensitizing-) leak. In ryanodine, SR Ca and Ca transient amplitude decay together, whereas, in caffeine, the amplitude of the Ca transient is preserved at low levels of leak. 135, 136

Does the SR membrane contain Ca?

Before considering mechanisms that may control Ca release from the SR, it is important to remember that the RyR does not sit in isolation in the SR membrane but, rather, forms a complex with triadin, junctin, and CSQ (calsequestrin). 91 CSQ is the major Ca buffer in the SR but has been suggested to have other effects because it, in addition to triadin and junctin, is required to make RyR open probability respond to luminal Ca, at least in bilayer studies. 92

Does Ca cycling take notice of flux balance?

Work on Ca cycling often takes insufficient notice of the flux balance condition. As discussed below, it is essential that postulated mechanisms and explanations are tested to ensure that they are compatible with the requirement for Ca efflux to equal influx such that steady state conditions can prevail.

What are the effects of potassium and calcium on the heart?

Effect of Potassium and Calcium Ions on Heart Function. In the discussion of membrane potentials, it was pointed out that potassium ions have a marked effect on membrane potentials, and it was noted that calcium ions play an especially important role in activating the muscle contractile process. Therefore, it is to be expected ...

What causes the heart to go into spastic contraction?

An excess of calcium ions causes effects almost exactly opposite to those of potassium ions, causing the heart to go toward spastic contraction. This is caused by a direct effect of calcium ions to initiate the cardiac contractile process, as explained earlier in the chapter.

What happens when potassium is too high?

Excess potassium in the extracellular fluids causes the heart to become dilated and flaccid and also slows the heart rate . Large quantities also can block conduction of the cardiac impulse from the atria to the ventricles through the A-V bundle. Elevation of potassium concentration to only 8 to 12 mEq/L—two to three times the normal value—can cause such weakness of the heart and abnormal rhythm that this can cause death.

Does calcium cause flaccidity?

Conversely, deficiency of calcium ions causes cardiac flaccidity, similar to the effect of high potassium. Fortunately, however, calcium ion levels in the blood normally are regulated within a very narrow range. Therefore, cardiac effects of abnormal calcium concentrations are seldom of clinical concern.

Does potassium affect the action potential of the heart?

These effects result partially from the fact that a high potassium concentration in the extracellular fluids decreases the resting membrane potential in the cardiac muscle fibers. As the membrane potential decreases, the intensity of the action potential also decreases, which makes contraction of the heart progressively weaker.