DISCUSS THE ROLE OF ION CURRENTS IN DETERMINING THE SHAPE AND DURATION OF CARDIAC ACTION POTENTIAL
Introduction
Selective permeability to various ions is an important characteristic of cell membranes, one that determines myriad cellular functions. In animal cells, ion permeability and the electrical potential generated thereof determines the activity of neurons, myocytes and the like. The electrical potential depends on the concentration of the ions inside and outside any given cell, the permeability of the cell membrane to the ions and the ion channels that are present on the surface of the cell. Cardiac cells also possess different ion channels on their surface. These determine the two types of electrical potentials, namely, resting membrane potential and action potential (Klabunde, 2013).
During resting conditions, the outside of the cell is more positive when compared to the inside of the cell. This potential is referred to as the resting membrane potential. When there occurs an influx of positive ions into the cells, this balance changes and the inside of the cell becomes more positive. Thus, an action potential is generated. The cardiac action potential refers to the different phases of electrical differences taking place in a single cardiac cell. An increase in the positive charge of the cardiac cells results in an elevated membrane potential. This change in electrical potential is known as depolarization. Repolarization occurs when cells return to the resting membrane potential (Shih, 1994).
Cells of the heart that can spontaneously initiate action potentials are called pacemaker cells. These cells are localized to the sinoatrial node, the atrioventricular node and the cells of the conducting system. Pacemaker cells have the unique ability to depolarize by themselves, a feature known as automaticity. Non-pacemaker cells are those which don’t possess the feature of automaticity (Golan, 2011).
The action potential of the heart begins in the right atrium after the excitation of the pacemaker cells of the sinoatrial node. Subsequent depolarization of adjacent cells occurs, as the current travels through them resulting in atrial excitation. As the current travels to the ventricles, the ventricular cells also get excited (Amin, et al., 2010)
The selective permeability of the cardiac cell membrane is elicited due to the presence of ion channels on the cell surface. These mediate the influx and efflux of charged ion into and out of the cell. The ion channels are not mere passages to mediate the influx and efflux of ions; they exhibit the feature of selective permeability. The selective permeability of ion channels is mediated by the size, valency and hydration of the ions. Apart from having a property of permeating ions selectively, ion channels have the capacity of gating. Gating of ion-channels can be voltage-dependent, mechano-sensitive or ligand-sensitive. Voltage- dependent ion channels open in response to differences in the membrane potential (Grant, 2009). The major ion-channels involved in cardiac action potential are sodium channels, potassium channels and calcium channels.
Phases of cardiac action potential
Action potential of cardiac cells has five distinct phases: phase 4, phase 0, phase 1, phase 2 and phase 3. Phase 4 refers to the phase with resting membrane potential with an electrical potential of -90V.
Phase 0
Phase 0 is a phase of fast depolarization. The resting membrane potential starts shifting from -90V due to the action potential generated by a neighbouring cell. The shift in the membrane potential occurs due to the opening of sodium ion channels. Influx of positive ion shifts the membrane potential to a slight positive range. During this phase, a type of calcium channels called L-type channels open leading to an influx of positive Ca+ ions (Ikonnikov and Yelle, 2014).
Phase 1
Aftre the depolarization that occurs in phase 0, there is a phase of temporary repolarization where the membrane potential shifts to zero due to the opening of voltage-gated potassium channels and the efflux of positive K+ ions.
Phase 2
Phase 2 in cardiac action potential refers to a long plateau phase. Two types of ion channels take part in this phase. There is an influx of calcium ions through the L-type calcium channels. On the other hand, there is an efflux of potassium ions through a type of potassium channels known as delayed rectifier channels. These two currents help in maintaining the membrane potential slightly below zero during the plateau phase.
Phase 3
In Phase 3 the resting membrane potential is slowly restored. The calcium channels are gradually inactivated while the potassium channels continue to pump K+ ions out of the cell. The membrane potential thus shifts towards -90mV, and the cell prepares for another cycle of depolarization and repolarization (Ikonnikov and Yelle, 2014).
Action Potential of Pacemaker cells
Since pacemaker cells can spontaneously elicit action potential there is a marked difference in the phases and ion currents involved in the generation of action potential in them. The pacemaker cells can be found in the sinoatrial node, the atrioventricular node and the Purkinje fibers (Jesperson, 2012). The pacemaker cells exhibit only phases 4, 0 and 3 of the five phases of action potential already discussed. Action potential in pacemaker cells is generated when there is a fall in the permeability of the cell to potassium ions, along with an exchange of sodium and calcium ions. At the threshold potential of -40 mV, L-type calcium channels open and the membrane potential falls to 0mV. Following depolarization, the permeability to potassium ions increases and the cell directly jumps to phase 3 repolarization (Pinnell, et al., 2007).
The action potential shows a marked difference among different species. Ventricular myocytes of rabbits show a transient outward current during phase 1. This phenomenon is not found to occur in the myocytes of guinea pigs. Myocytes of rats also exhibit an outward current during phase 1, but in these cells, the plateau phase of repolarization is not well-defined. These differences in the action potential exist mainly because of the differential action of calcium and potassium currents (Varro, et al., 1993).
The Different Currents Involved in Cardiac Action Potential
The ‘funny’ current
The main feature that distinguishes pacemaker cells in the sinoatrial node from the working myocytes is their ability to elicit action potential spontaneously. These cells undergo depolarization during the phase 4 of the action potential, enabling the continuous firing of action potential in heart cells. The current responsible for this mechanism was initially thought to be an outward K+ current. This perception changed with the discovery of a new current, termed funny current. This current was originally characterized in the cells of the sinoatrial node (Brown, et al., 1979). The activation of the funny current is elicited at negative membrane potentials of about -40mV. This voltage synchronized with the voltages at which pacemaker cells depolarize (DiFransesco, 1986). Thus, the funny current was established as the major current responsible for the pacemaker activity of the cells of the sinoatrial node. Pacemaker cells possess a type of ion channels on their surface, known as hyperpolarization-activated cyclic nucleotide-gated ion channels (HCNs). There are four known members of HCN channels. These ion channels conduct sodium and potassium ions. A membrane potential of -55mV activates these channels leading to depolarization (Shi, et al., 1999). The current elicited by the HCN channels are called If currents. The If currents are responsible for the generation of spontaneous action potential in pacemaker cells. Several mutations of funny channels have been characterized some of which are :
1) Substitution of the amino acid leucine at position 573 (L573X) of the HCN4 protein results in cardiac arrhythmia. This mutation renders the channel insensitive to cAMP causing abnormalities in the conduction of ions. As a result, there is impaired depolarization in the pacemaker cells of the sinoatrial node (Schulze-Bar, et al., 2003).
2) Substitution of apratate at the 553rd position of the HCN4 protein to asparagine causes abnormal intracellular trafficking of the protein. Therefore, there are reduced numbers of HCN4 channels of the surface of cardiac cells. Reduction in the number of HCN channels leads to a decrease in If currents. The D553N mutation has 100% correlation to the phenotypic condition of bradycardia. Some patients with the mutation have shown symptoms like long QT and polymorphic ventricular tachycardia, but the percentage of correlation is not complete (Ueda, et al., 2004)
Cardiac sodium channels and Na+ currents
The sodium channel of heart cells is voltage-gated and is composed of two subunits: one subunit and two subunits (Bezzina, et al. 2001). The subunit is encoded by the SCN5A gene and contains four domains each made up of six transmembrane domains (Wang, et al. 1996). These four domains are organized in such a way as to form a central ion-conducting pore. The pore is lined by a protein structure known as the P-loop, which is responsible for the selective conductance of the ion channel (Sato, et al., 1998). Sodium channels are sensitive to the toxin tetrodotoxin (Lin, et al., 2011).
There are two major sodium currents: the INa and the INaL. Depolarization and the generation of action potential occur due to the action of the INa also known as the excitatory sodium current. The INa is active only during the initial phase 0 (Fujii, et al. 1988). The late sodium current, on the other hand, is involved in the repolarization of the heart and persists till the plateau phase. The late Na current is expressed in a variety of cell types in different kinds of organisms. It is expressed in the atrial myocytes of rabbit and man, the ventricular myocytes of dog and guinea pig and the Purkinje fibres of dog and rabbit (Zaza, et al. 2008). The cardiac sodium currents show marked differences in adult and immature heart tissues. The sodium currents are found at increased concentration in adult heart when compared to paediatric heart. Paediatric heart cells display delayed closure of sodium channels, which leads to an increased influx of sodium ions into the cytoplasm. The increased ion influx results in the longer action potential characteristic of paediatric heart (Cai, et al., 2011).
There are several conditions that are correlated to the improper functioning of sodium ion channels.
1) Long Q-T syndrome
Long Q-T syndrome (LQTS) is an inherited heart disorder that is characterized by ventricular tachyarrhythmias and ventricular fibrillation. In this disease, there is delayed repolarization of cardiac muscle cells. LQTS is an autosomal dominant disorder (Wang, et al., 1996). LQTS3 is a form of this disorder and arises due to mutations in the SCN5A gene. Nine different mutations of different types have been associated with the disease. Mutations in the gene results in protein channels with altered functions. Three of the mutations, KPQ (a change in the amino acid sequence) (Bennett, et al., 1995), N1325S (amino acid substitution) (Yong, et al., 2007) and R1644H (Wang, et al., 1996) causes the channel to open during the late phase of depolarization, leading to an increased inward sodium current. The persistent inward current is the cause for the delayed repolarization of ventricular myocytes associated with LQTS.
2) Brugada Syndrome
Another inherited disorder involving improper functioning of the sodium channel is the Brugada syndrome. This disease occurs due to mutation in the SCN5A gene or in the genes that encode other regulatory proteins involved in the synthesis and sub-cellular trafficking of the ion channel (Brugada and Brugada, 1992). The ECG of patients with Brugada syndrome shows an S-T segment elevation brought about by an increase in the outward current or a decrease in the inward current. This change in the flow of current occurs at the end of phase 1. Several of mutations of the SCN5A gene have been associated with Brugada syndrome. A threonine to isoleucine mutation at position 353 of the protein causes reduced trafficking of the protein to the sarcolemma. Consequentially, there is reduction in sodium currents leading to severe arrhythmia (Pfahnl, et al., 2007).
3) Progressive Cardiac Conduction Disorder (PCCD)
PCCD is a disorder in which there is an abnormal conductance of ion currents through the His-Purkinje conduction system. This disease occurs due to a splice-site mutation in SCN5A gene that leads to a reduction in the transient inward sodium currents that are activated in response to depolarization. The disease is characterized by degeration of the His-Purkinje system and complete atrioventricular block (Probst, et al., 2003).
Some acquired heart diseases have also been associated with abnormal sodium currents. Atrial Fibrillation (AF) has been found to occur due to a reduction in sodium channels and the subsequent reduction of INa. Reduction in Ina and enhancement of INaL has been observed in the case of heart failures. Abnormal gating of sodium channels is known to reduce INa in myocytes during myocardial infarction (Nattel, et al., 2007).
Like the sodium channels, the potassium channels are also made of and subunits. Several genes have been found to encode for the different subunits of the potassium channels. On a broad scale, there are three families of proteins that act as cardiac potassium ion channels. The first family consists of those that possess six transmembrane domains with a single pore. Examples of this family include the Kv channels, the ERG channels and the KCNQ channels. The second family of potassium channels include the inward rectifier channels. The K1 channel, the KATP channel and the KAch channels belong to this family. These channels play important roles in repolarization by inducing inward potassium currents. The K2P channels represent the third family of ion channels and have two pore channels (Synders, 1999).
- The Potassium Currents: The Transient Outward Current (Ito)
The Ito current is activated in response to depolarization and causes the early repolarization phase of cardiac action potential. The Ito current is the sum of two different currents: the Ito1 (calcium independent) and the Ito2 (calcium dependent). The role of the latter in cardiac potential is less characterized (Oudit, et al., 2001). However, Ito1 is known to determine the peak of the action potential at the plateau phase and determines the Ca-Na exchange. The activity of Ito1 is more in the midmyocardial and epicardial cells and less in the endocardial cells. The Ito1 currents are elicited by Kv4.3 ion channels. The drug 4-aminopyridine (4-AP) blocks the action of It01 currents. Inside the cell, this current is regulated by phosphorylation mediated by protein kinases like protein kinase A (PKA) and protein kinase C (PKC). Ito1 current is more expressed in the ventricles of dogs and humans while rarely active in the ventricles of guinea pigs. Also, this current is active more in the epicardium than the endocardium in both humans and canines (Feng, et al., 1998).
- The Potassium Currents: The Delayed Rectifier Current
There are three variations of the delayed rectifier currents. This classification is based on the speed of action. The three kinds of rectifier currents (Ik) are as follows:
The IKur is the ultra rapid form of the delayed rectifier current. This current is active mainly during the plateau phase. The IKur plays an important role in the repolarization of atrial myocytes. However, this current hasn’t been recorded in the ventricular cells. The IKur current is transmitted through the action of the Kv1.5 channel. This channel has been found in both human and rat hearts. Intracellular regulation of IKur is brought about by the concentration of K+ ions and the action of cyclic AMP (adenosine monophosphate) (Wang, et al., 1993).
The Ikr current is the rapid acting component of the delayed rectifier currents. IKr is active both in the atrial and the ventricular cells of the human heart. Interestingly, it has been noted that in humans, the expression of IKr is more in the ventricles whereas in rats it is highly expressed in atrial cells as compared to the ventricular cells. This current is transmitted through the HERG channels. The subunit of the HERG channel is encoded by the KCNH2 gene. Another gene called the KCNE2 codes for a different regulatory subunit on the protein that is responsible for the transmission of the current (Sanguinetti, et al., 1990).
The third component of the delayed rectifier current is the slow acting current IKs. This current is responsible for the repolarization of the atrial and the ventricular cells of the human heart (O’Hara and Rudy, 2012). The importance of the IKs current can be highlighted by explaining its role in the heart-rate dependent shortening of action potential. When there is an increase in the heart rate, there is a delay in the deactivation of potassium channels. Thus, the channels remain open for a longer duration leading to increased repolarization. The genes that encode the different components of the IKs channel are KCNQ1 and KCNE1. The IKs ion channel is regulated by phosphorylation by different intracellular protein kinases). The IKs current is more active than Ikr in guinea pig, but vice-versa in humans and cats (Yang and Sigworth, 1998).
- The Potassium Currents: The Inward Rectifier Current (IK1)
IK1 is a current that is active at different ranges of membrane potentials. This current is active at negative membrane potentials and closes during depolarization. The channels reopen at membrane potentials close to -20mV and plays crucial roles in the phase 3 of cardiac action potential. IK1 is active more in the ventricular cells as compared to the atrial cells and is decreased in pacemaker cells. The IK1 current is transmitted through the Kir2.1 channel, which is encoded by the KCNJ2 gene (Schram, et al., 2002).
- The Potassium Currents: The IKATP Current and the IKAch
The ATP-sensitive potassium channels are those that are regulated by adenosine triphosphate. The KATP is composed of four channel subunits and four regulatory subunits. Two of the regulatory subunits are called SUR1 and SUR2. In mouse hearts, SUR1 is expressed in the atria while SUR2 is expressed in the ventricles. In the human heart, the reverse happens (Glukhov, et al., 2010). The IKAch is a K+ current that is activated by acetylcholine (Katz, 1993). This channel is regulated by G-protein and was first isolated from rats.
- The Potassium Currents: IKp channels
The IKp current has been characterized in guinea pig hearts and acts as a small conductance. The protein subunits involved in this type of conductance is yet to be functionally characterized (Yue and Marban, 1988).
The diseased conditions that occur due to the improper functioning of potassium channels are as follows:
1) Long Q-T Syndrome subtype 1 (LQT1) and subtype 5 (LQT5)
This condition arises due to a mutation in the KCNQ1 gene, which codes for the channel that transmits the slow-acting IKs current. Mutation in this gene results in a reduced efflux of potassium ions leading to enhanced repolarization. This syndrome is characterized by a broad-based T wave in the ECG of the patients affected with it. LQT5 is another variation of LQTS and occurs when there is a mutation in KCNE1 gene. This mutation also causes abnormalities in the slow-acting IKs current (Schwartz, et al., 2006).
2) LQT7 is a subtype of LQTS caused by a mutation in the KCNJ2 gene and disrupts the function of the inward rectifying current Ik1. There is a reduced potassium efflux and prolonged QT interval (Tristani-Firouzi, et al, 2008).
3) LQT2 is another subtype of LQTS that arises due to a mutation in the HERG gene (Anderson, et al., 2006). As a result, there is a loss-of-function of the channel that transmits the delayed rectifier current IKr. Prolonged repolarization occurs and shows as long QT interval in the ECG.
The different types of LQTS that arise as a result of abnormalities in potassium currents are summarized in the table below.
SQTS is an inherited cardiac disorder characterized by short QT intervals in the ECG. SQTS arises as a result of gain-of-function mutations in the cardiac ion channels. Some characterized mutations are N588K in the KCNH2 gene (Schwatrz, et al., 2004), V307L in the KCNQ1 gene (Bellocq, et al., 2004) and G514A in the KCNJ2 gene (Priori, et al., 2005). Based on the gene in which the mutation occurs, SQTS is classified into three subtypes: SQTS1, SQTS2 and SQTS3. This syndrome is characterized by rapid repolarization brought about by increased IKr, IKs or IK1 (Giudicessi and Ackerman, 2012).
5) Brugada Syndrome
Brugada syndrome is an inherited disorder that is characterized by an elevation in the ST segment of the ECG. This syndrome arises as a result of a persistent Ito current in the epicardial cells of the ventricle. Brugada Syndrome is a J-wave syndrome in which there occurs an abnormality in the J-wave of the ECG. The J-wave marks the beginning of repolarization. This abnormality arises due to mutations in various genes, some of which code for subunits of calcium ion channels. An amino-acid substitution (S422L) mutation in the KATP channel prevents the channel from closing on time (Medeiros-Domingo, et al., 2010). Brugada Syndrome has also been associated with mutations in the KCNE3 gene, the KCND3 gene and the KCNIP2 gene (Giudicessi and Ackerman. 2012).
Several other mutations in potassium ion channels have been associated with various arrhythmias. Dipeptidyl-aminopeptidase-like protein-6 is a protein that modulates the function of the Kv4.3 potassium channel. Studies in patients with idiopathic ventricular fibrillation found a mutated DPP6 gene which resulted in an overexpression of the gene leading to a decrease in Ito (Alders, et al., 2009). Myocardial infarction is characterized by a reduced Ito, brought about by calcineurin over-activation (Nattel, et al., 2007).
Calcium channels and Ca currents
Cardiac muscles possess two types of calcium channels on their surface, both of which are involved in the regulation of the flow of calcium ions during action potential generation. These two classes are known as L-type calcium channels and T-type calcium channels (Williams, 1997). The role of calcium during the generation of action potential has two functionally different characters. The influx of calcium ions helps in keeping the membrane potential towards a positive range (Nilius, et al., 1985). Apart from this, calcium acts as a second messenger for the excitation-contraction coupling process.
L-Type channels and the ICa,L current
The L-type or low threshold type channels are complex structures with, and subunits (Bodi, et al. 2005). The L-type channel produces the ICa,L current that is activated and inactivated at a positive membrane potential. The activation of ICa,L depends on the calcium concentration and the voltage across the cell (Ellis, et al., 1988). The calcium current generated by the L-type channels is partly responsible for the plateau phase of action potential. The flow of calcium ions also helps in the pacemaker activity of nodal cells.
T-type channels and the ICa,T current
T-type calcium channels are low-voltage activated ion channels. They are composed of pore-forming subunits. In cardiac cells, two variations of the T-type channels are found to occur: the Cav1.2 and the Cav1.3 channels. The T-type channels operate at negative membrane potentials. These channels are activated at a threshold potential of -70mV and get activated at membrane potentials of -30mV to -10mV. The activation of T-type calcium channels is not dependent on the concentration of calcium ions. In adult human heart, the density of the T-type calcium channels and currents is found to be higher in the pacemaker cells that are localized to the conduction system (Sipido, et al., 1998). The density of the ICa,T current is different in different species of mammals. The density is found to be higher in smaller mammals and decreases with an increase in the body mass. The T-type channels have a low conductivity to Ba ions.
The T-type channels are less prominent in the cells of the ventricle when compared to atrial cells. Pacemaker cells have a considerable amount of T-type channels suggesting their role in generating pacemaker action potential (Ono and Iijima, 2010).
A B
B-Canine Purkinje Fibre showing Land T-type calcium currents
There are various inherited and acquired disorders that are associated with abnormalities in calcium ion channel functioning. Some of them are listed below:
1) Timothy Syndrome
Timothy Syndrome is an inherited disorder that manifests multi-organ symptoms including cardiac arrhythmia and syndactyly (Splawsky, et al. 2005). Timothy Syndrome is a type of LQTS, also known as LQT8. Timothy Syndrome arises as a result of G406R amino acid substitution mutation in the human L-type calcium channel CaV1.2. The mutation occurs in the CACNA1C gene. This mutation impairs the voltage-dependent inactivation of the calcium channel resulting in increased calcium concentrations. Two types of substitutions have been characterized in relation with Timothy Syndrome. Both these mutations involve the glycine amino acid at position 402 of the protein. Both these substitutions are gain-of-function mutations (Splawsky, et al. 2005). The decreased inactivation of the calcium channel causes a sustained inward current during the plateau phase of action potential. As a result, the repolarization is delayed.
2) Brugada Syndrome
Several mutations in calcium channels have been associated with Brugada Syndrome:
- Mutations in the CACNA1C gene that codes for the subunit of the Cav1.2 channel. Some examples of the mutations are G490R and A39V (Burashnikov, et al., 2007).
- A missense mutation S481L in the CACNB2 gene that codes for the subunit of the Cav1.2 channel (Cordeiro, et al., 2009).
3) Catecholaminergic polymorphic ventricular tachycardia
CPVT is a disorder that arises due to RyR2 mutations in ion channels. Mutations in these channels cause abnormal leakage of calcium ions into the cytoplasm of heart cells. This increase in calcium ions enhances the rate of exchange of calcium and sodium ions during phase 4. As a result, a depolarization event occurs during the phase 4 of cardiac action potential (Priori, et al., 2001).
Ion Currents during Heart Failure
During heart failure, electrical instability is observed. In the human heart, heart failure is characterized by a prolonged action potential. The currents involved in the plateau phase are thought to be responsible for this abnormal action potential. The main currents that come into play during this time are Ito1, ICa,L, ICa,T and IKr. Increase in any inward current or decrease in any outward current or both together brings about the prolonged action potential associated with heart failure (Kaab and Nabauer. 2001).
Conclusion and Future Prospects
Cardiac action potential is an important area of study with huge medical implications. The changes in the electrical activity of the heart are brought about by the variations in the conductance of ions into and out of the heart cell. The ions could be positively or negatively charged and they move across the cell-membrane based on the electrical potential inside and outside the cell. Though the action potential and the ion currents involved in generating it are similar in different species, there are subtle differences. A treatment of human and mouse hearts with two drugs highlights these differences. Human and mouse hearts were treated with Diazoxide and Pinacidil. Diazoxide was found to act on the action potential only in the atrial cells of the mouse heart. The same result was not repeated in human hearts. This difference occurs due to the presence of different subunits of the potassium ion channel IKATP in the two species (Lutz, 2011). Studying these differences is important from a medical point-of-view because, in most cases mouse and guinea pig models are used to study human pathological conditions. Assuming that the basic physiology in the model organisms is the same as that of humans might lead to immense complications. To avoid this, it is essential to highlight the similarities and differences in the cardiac physiology of humans and model organisms.
This paper discussed the action of three major types of ions in cardiac action potential: sodium ions, calcium ions and potassium ions. The role of these ions in healthy and diseased hearts has been discussed. The study of ionic conductance and the discrepancies associated with them are important in treating the cardiac disorders. For this purpose, attempts have been made to characterize the genes that are involved in bringing about changes in ionic conductance. This approach further helps in employing gene-based therapeutic strategies in the treatment of inherited heart diseases. Identification of mutations underlying other uncharacterized heart disorders might help in curing them. An understanding of the basic action of electrical conductivity in heart is essential. Cure of a disease becomes possible with the study of its physiology, genetics and molecular biology.
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