Startseite Ventricular ion channels and arrhythmias: an overview of physiology, pathophysiology and pharmacology
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Ventricular ion channels and arrhythmias: an overview of physiology, pathophysiology and pharmacology

  • Shiqi Liu ORCID logo , Wei Wang ORCID logo , Yang Yang EMAIL logo und Zhuo Huang EMAIL logo
Veröffentlicht/Copyright: 3. März 2025
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Medical Review
Aus der Zeitschrift Medical Review Band 5 Heft 3

Abstract

Cardiac ion channels are critical transmembrane proteins that mediate almost all aspects of cardiac function including generation and propagation of cardiac action potential (AP) as well as maintenance of normal heart excitability and contraction. In addition, the pivotal role of cardiac ion channels in cardiac health and disease is underscored by the profound effects of their dysfunctional mutations on various arrhythmias. Hence, ion channels are vital targets for antiarrhythmic drugs. In this review, we first summarize the characteristics, structure of the various cardiac ion channels and their specific roles in cardiac electrophysiology. Subsequently, we highlight the implications of genetic mutations that disrupt ion channel function, which are associated with inherited cardiac arrhythmias. Finally, we address antiarrhythmic drugs acting on cardiac ion channels respectively, according to their therapeutic targets. In conclusion, this manuscript aims to review the physiology, pathophysiology and pharmacology of the most prominent ventricular NaV, CaV, KV, and Kir ion channels.

Keywords: ion channels; action potential; arrhythmias; antiarrhythmic drugs

Introduction

Ion channels are ubiquitous transmembrane proteins embedded within living cells, selectively permitting the passage of charged ions (e.g., sodium, potassium, calcium, and chloride) across the cell membrane. These orchestrated movements of ions, driven by electrical and chemical gradients, underpin a myriad of physiological processes, including cellular secretion, nerve signal transmission, and muscle contraction.

Meanwhile, the rhythmic and coordinated contraction of the heart are governed by the precise flow of ions across the cell membranes. This electrical activity is shaped by a complex interplay of various ion channels, with specific channels responsible for the distinct phases of cardiac action potential (AP). Cardiac AP originates in the sinoatrial node (SAN) and travels through the specialized conduction system, ensuring coordinated contraction of the atria and ventricles [1].

These numerous ion channels expressed in the heart or in the vasculature are the target for clinical antiarrhythmic drugs. Understanding the functions and dysfunctions of cardiac ion channels, as well as their impact on the cardiac AP, is of paramount importance for treating inherited arrhythmias. In the following chapters, we aim to briefly discuss the structure, expression profiles, physiological roles and pharmacology of predominant subtype of NaV, CaV, KV, and Kir channels which contribute to ventricular AP.

Fast action potential of cardiomyocytes

In ventricular myocytes, cardiac AP depolarizes rapidly due to a high density of voltage-gated sodium NaV1.5 channels which allow sodium ions to enter cardiac cells within 1 ms. This fast response AP can be divided into five distinct phases (P0–P4) that are facilitated by different cardiac ion channels [2] (Figure 1).

Figure 1: Fast action potential and ionic currents. Schematic of the five phases (0, 1, 2, 3 and 4) of the fast AP. The contribution of different ion channels to the generation of a fast AP and their representative antiarrhythmic drugs are included. The segments with different color represent the corresponding time periods of different currents in the fast AP. I Na, voltage gated sodium current. I Ca, voltage gated calcium current. I to, transient outward potassium current. I Ks, slow delayed rectifier potassium current. I Kr, rapid delayed rectifier potassium current. I k1 , inward rectifier potassium current.
Figure 1:

Fast action potential and ionic currents. Schematic of the five phases (0, 1, 2, 3 and 4) of the fast AP. The contribution of different ion channels to the generation of a fast AP and their representative antiarrhythmic drugs are included. The segments with different color represent the corresponding time periods of different currents in the fast AP. I Na, voltage gated sodium current. I Ca, voltage gated calcium current. I to, transient outward potassium current. I Ks, slow delayed rectifier potassium current. I Kr, rapid delayed rectifier potassium current. I k1 , inward rectifier potassium current.

Phase 4 represents the resting state of APs during which ventricular cells maintain a resting membrane potential (-90 mV). The outward I K1 current [3] facilitated by the inward rectifier potassium channels (Kir2.1/2.2) is the primarily current that mediate this phase. Phase 0, the fast depolarization, occurs as myocardial cells are excited by appropriate stimulation, which triggers the opening of voltage-dependent sodium channels (NaV1.5) and the entry of sodium ions. Then, the membrane potential shifts from resting state (-90 mV) into positive voltage range (+30 mV) [4]. Phase 1 presents an initial and rapid repolarization induced by the inactivation of sodium channels and transient outward potassium currents I to mediated by voltage-dependent potassium channels (KV4.2/4.3, KV1.4). The outward I to current conduces the membrane potential to decline to about 0 mV. During Phase 2, or the plateau, calcium ions enter the cells through the L-type voltage-gated calcium channels (CaV1.2/1.3), while the voltage-dependent potassium channels (KV11.1, KV7.1) produce the outward I Kr and I Ks currents which is approximately equal to I Ca. Phase 3 shows the rapid terminal repolarization facilitated by the increased outward I Kr and I Ks currents as well as the lessened inward I Ca. Then the Kir channels (Kir2.1/2.2) mediate the I K1 currents that complete repolarization phases, allowing the membrane potential to return to its resting state.

Arrhythmogenic ventricular ion channels

The voltage variations in cardiac AP are generated by ions flowing through specific selectively permeable ion channels whose dysfunctions are associated with cardiac arrhythmias [5], 6]. Here, we list the clones of the α subunits of the major arrhythmogenic ventricular ion channels (Table 1). In particular, these ion channels are the main therapeutic targets of antiarrhythmic drugs. Meanwhile, the tremendous development in structural and molecular biology has significantly facilitated the investigation of protein structures and the elucidation of drug-binding sites.

Table 1:

Main arrhythmogenic ventricular ion channels and their currents, genes and functional phases in fast action potential [4].

Current Ion Direction Functional phases α subunits Gene
I Na Na+ Inward Phase 0 NaV1.5 SCN5A
I to,fast K+ Outward Phase 1 KV4.2/KV4.3 KCND2/KCND3
I to,slow K+ Outward Phase 1 KV1.4 KCNA4
I Ca,L Ca2+ Inward Phase 2 CaV1.3/CaV1.2 CACNA1D/CACNA1C
I Kr K+ Outward Phase 2, 3 KV11.1 KCNH2
I Ks K+ Outward Phase 2, 3 KV7.1 KCNQ1
I K1 K+ Outward Phase 3, 4 Kir2.1/Kir2.2 KCNJ2

  1. I to,fast, fast transient outward potassium current; I to,slow, slow transient outward potassium current.

Voltage-dependent sodium channels

In cardiac myocytes, the NaV1.5 channel is the predominant subtype of voltage-gated sodium channels family (NaV1.1–1.9). The channel exists as a protein complex consisting of a large α subunit (>260 kDa) encoded by the SCN5A gene, along with β1 and β2 subunits, encoded by SCN1B and SCN2B, respectively [13]. The α subunit consists of four homologous domains (DI–DIV) [14] and it is the major functional subunit capable of independently forming channels and generating sodium current [15]. Each domain contains six transmembrane segments (S1–S6), and the S4 segment acts as the voltage sensor domain (VSD). The extracellular loops (P loops) between the S5 and S6 segments of four homologous domains form the pore region, where the Asp (D), Glu (E), Lys (K), Ala (A) residues from each domain contribute to the selectivity filter of the sodium channel [16] (Figure 2B).

Figure 2: Cardiac voltage-gated sodium channel (NaV1.5) and its typical gain-of-function or loss-of-function SCN5A mutations. (A) schematic representation of I Na corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) schematic of NaV1.5 protein structure and some typical GOF and LOF mutations [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. NaV1.5 comprises one α subunit consisting of four homologous domains (DI-DIV) and one or two auxiliary β subunits. The transmembrane segments S1-S6 in each domain are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.
Figure 2:

Cardiac voltage-gated sodium channel (NaV1.5) and its typical gain-of-function or loss-of-function SCN5A mutations. (A) schematic representation of I Na corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) schematic of NaV1.5 protein structure and some typical GOF and LOF mutations [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. NaV1.5 comprises one α subunit consisting of four homologous domains (DI-DIV) and one or two auxiliary β subunits. The transmembrane segments S1-S6 in each domain are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.

NaV1.5 channels are closed in the resting state. In response to membrane depolarization, these channels generate a depolarization within 200–300 μs and the majority are inactivated rapidly within 2–5 ms [13], while a small number of channels remain in open state in the later phases, contributing to late sodium current (late sodium current, I Na, Late). Though I Na, Late is only about 5 % of the I Na peak current, it still plays a significant role in maintaining the AP plateau phase and duration [33], 34].

Due to the crucial role of the NaV1.5 channel in cardiac AP, many mutations in the SCN5A gene are associated with inherited arrhythmogenic diseases (IADS), including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), sick sinus syndrome (SSS), dilated cardiomyopathy (DCM), atrial fibrillation (AF), and progressive cardiac conduction disease (PCCD) [24]. To date, more than 700 SCN5A mutations have been identified as being related to cardiac diseases. Among them, LQT3 is characterized by prolonged QT intervals, accentuated QT dispersion, late onset of T wave and frequent prominent U wave which is related to over 300 SCN5A variants. Five to ten percentage of LQT3 patients possess gain-of-function variants in SCN5A resulting in a more rapid AP initiation and enhancing I Na, Late. On the other hand, loss-of-function variants in SCN5A cause synthesis deficiency or trafficking defects, permeation disruption, slower activation or faster inactivation of NaV1.5 channels. These dysfunctional behaviors primarily induced BrS which is characterized by ST segment elevation on electrocardiogram (ECG). These loss-of-function mutations ruin the transmembrane ion flux balance and damage the depolarization in phase 1 (Figure 2). In addition, ischemic cardiomyopathy, myocardial infarction and heart failure are associated with reduced Nav1.5 peak current or enhanced late current through metabolic changes or specific signaling pathways, contributing to arrhythmic risk [35], [36], [37].

Therefore, the NaV1.5 channel is a crucial therapeutic target for antiarrhythmic medications. The updated Singh–Vaughan Williams classification system [38] categorizes antiarrhythmic drugs into five classes (Class I–V) based on their primary mechanisms of AP. Class I antiarrhythmic drugs (Table 2), also known as sodium channel blockers, constitute the largest group and are further subdivided into Ia, Ib, and Ic subclasses based on the distinct effects on sodium current [39]. Moreover, a growing body of evidence has implicated the late sodium current (I Na, Late), which remains during the late phases of the AP, in the pathogenesis of various arrhythmias, including AF and LQT3. Ranolazine, a selective blocker of I Na, Late current without significantly affecting I Na current, has been identified as Id antiarrhythmic drug demonstrating efficacy in treating AF, LQT3 and heart failure [7], 8].

Table 2:

Class I antiarrhythmic drugs [7], [8], [9], [10].

Class Drug exemplars Pharmacological targets Therapeutic action Clinical indications
Ia Quinidine NaV1.5 channel open state blocker; intermediate (τ ≈ 1–10 s) dissociation kinetics; often concomitant K+ channel block Reduces peak I Na, AP generation and (dV/dt)max; slows action potential conduction down; often accompanies I K inhibition and prolongs APD, ERP, QT interval Supraventricular tachyarrhythmias, recurrent atrial fibrillation; ventricular tachycardia, ventricular fibrillation (SQTS and BrS)
Procainamide
Disopyramide
Ib Lignocaine NaV1.5 channel open state blocker; rapid (τ ≈ 0.1–1 s) dissociation kinetics Reduces peak I Na, AP generation and (dV/dt)max; slows action potential conduction down; prolongs APD, ERP Ventricular tachyarrhythmias; ventricular fibrillation (particularly after myocardial infarction)
Mexiletine
Ic Propafenone NaV1.5 channel inactivated state blocker; slow (τ ≈ 0.1–1 s) dissociation kinetics Reduces peak I Na, AP generation and (dV/dt)max; slows action potential conduction down; reduces overall excitability; prolongs APD (at high heart rates) and ERP Supraventricular tachyarrhythmias; premature ventricular contraction; ventricular tachyarrhythmias resistant to other treatment in the absence of structural heart disease; CPVT
Flecainide
Id Ranolazine NaV1.5 channel I Na, Late blocker Reduces I Na, Late; affects AP plateau, duration and QT interval Stable angina; ventricular tachycardia; LQT3; AF; heart failure

Beyond the well-characterized NaV1.5 channel, the heart harbors a diverse array of additional sodium channels, including NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.6, NaV1.8, and NaV2.1 [13]. While their precise roles in cardiac physiology remain to be fully elucidated, emerging evidence suggests that these channels play crucial yet often underappreciated roles in regulating electrical activity and contributing to various cardiac pathologies.

In heart failure, NaV1.1 channel expression is significantly upregulated in ventricular cardiomyocytes [40], contributing to the I Na, Late current. Similarly, NaV1.8 channel expression is upregulated in cases of cardiac hypertrophy and heart failure [41]. Blocking NaV1.8 currents reduces I Na, Late and shortens AP duration [42], suggesting that NaV1.8 channel contributes to I Na, Late current and plays a potential role in regulating cardiac excitability. Notably, many mutations in SCN10A gene which encodes the NaV1.8 channel have been reported in patients with AF [43] and sudden cardiac death [44].

Voltage-dependent calcium channels

In 1989, Reuter first reported the existence of two distinct types of voltage-gated calcium (CaV) channels in mammalian hearts: T-type and L-type voltage-gated calcium channels [45], 46]. Cardiac CaV channels are composed of a pore-forming α1 subunit along with auxiliary β and α2δ subunits, while lacking the γ subunit found in skeletal muscle CaV channels (Figure 3B). Among these, the L-type voltage-gated calcium channel CaV1.2 encoded by the CACNA1C gene is the predominant α1 subunit in cardiac system [47], 48], which requires assembly with auxiliary β and α2δ subunits to function properly [1].

Figure 3: Cardiac L-type voltage-gated calcium channel (CaV1.2) and its typical gain-of-function or loss-of function CACNA1C mutations. (A) schematic representation of I Ca,L corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) schematic of CaV1.2 protein structure and some typical GOF and LOF mutations [49], [50], [51], [52]. CaV1.2 comprises one α subunit consisting of four homologous domains (DI-DIV). The transmembrane segments S1-S6 in each domain are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.
Figure 3:

Cardiac L-type voltage-gated calcium channel (CaV1.2) and its typical gain-of-function or loss-of function CACNA1C mutations. (A) schematic representation of I Ca,L corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) schematic of CaV1.2 protein structure and some typical GOF and LOF mutations [49], [50], [51], [52]. CaV1.2 comprises one α subunit consisting of four homologous domains (DI-DIV). The transmembrane segments S1-S6 in each domain are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.

The structure of the CaV1.2 channel resembles that of the NaV channel [53], 54]. The α1 subunit consists of four homologous domains (DI–DIV), each containing six transmembrane helices (S1–S6). The S4 segment serves as the voltage sensor domain (VSD), S5 and S6 segments form the structure of pore region. The glutamate residues (EEEE) in the four extracellular loops constitute pore filter and determine the ion selectivity of calcium channels [55]. I Ca,L current contributed by CaV1.2 channels plays a crucial role in maintaining the plateau of AP and in excitation–contraction coupling of cardiomyocytes [12], 56].

As reported, G406R and G402S mutations in CACNA1C gene are associated with Timothy syndrome (TS) which is often accompanied with long QT syndrome 8 (LQT8), ventricular arrhythmias and structural heart disease [56]. These gain-of-function (GOF) mutations lead to delayed inactivation of the I Ca,L current [56] and enhance gating coupling [57] of the CaV1.2 channel. In addition, the loss-of-function (LOF) mutations, such as A39V and G490R, drastically reduce the amplitudes of I Ca,L current, resulting in familial cardiac arrhythmia syndromes [49] (Figure 3).

The Singh-Vaughan Williams classification initially defined Class IV antiarrhythmic drugs as non-dihydropyridine calcium channel blockers [9]. This concept has since been expanded to drugs acting on calcium homeostasis related targets. The traditional surface membrane Ca2+ channel blockers are classified as Class IVa (Table 3), while the updated classification includes Intracellular Ca2+ channel blockers (Class IVb), sarcoplasmic reticular Ca2+-ATPase activators (Class IVc), surface membrane ion exchange inhibitors (Class IVd), and phosphokinase and phosphorylase inhibitors (Class IVe). However, no clinical drugs are currently available for Class IVc, IVd, and IVe.

Table 3:

Class IVa antiarrhythmic drugs [9], 11].

Class Drug exemplars Pharmacological targets Therapeutic action Clinical indications
IVa Bepridil Nonselective surface membrane Ca2+ channel blockers Reduces I Ca, resulting in inhibition of SAN pacing, inhibition of AVN conduction; prolongs ERP, APD, PR interval; diminishes repolarization reserve and suppression of intracellular Ca2+ signaling Angina pectoris; supraventricular tachyarrhythmias
Verapamil Selective L-type Ca2+ channel blockers Reduces I Ca, resulting in inhibition of SAN pacing, inhibition of AVN conduction; prolongs ERP, APD, PR interval; diminishes repolarization reserve and suppression of intracellular Ca2+ signaling Supraventricular arrhythmias and ventricular tachycardia (without structural heart disease); rate control of atrial fibrillation
Diltiazem
– Selective T-type Ca2+ channel blockers Inhibition of SAN pacing; prolongs His-Purkinje phase 4 repolarization –

Voltage-dependent potassium channels

Voltage-gated potassium channels (KV) share similar structural compositions, consisting of α-subunits which form the pore region of channels and multiple auxiliary β subunits. In contrast to NaV channels which are homotetramers, KV channels are hereotetramers composed of four distinct α subunits. Each α subunit consists of six transmembrane helices (S1–S6), in which S4 segment serves as the voltage-sensing domain, while the extracellular domain between S5 and S6 forms the pore region. The conserved threonine (T), valine (V), glycine (G), tyrosine (Y), and glycine (G) residues on each P-loop create a narrow pore filter determining its potassium ion selectivity [11] (Figure 4B, Figure 5B, and Figure 6B).

Figure 4: Cardiac voltage-gated potassium channel (KV4.3) and its typical gain-of-function or loss-of function KCND3 mutations. (A) Schematic representation of I to corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) Schematic of KV4.3 α subunit structure and some typical GOF and LOF mutations [58], [59], [60], [61]. KV4.3 comprises four α subunits which are heterotetramers and interacting auxiliary subunits. Each α subunit consists of six segments (S1-S6) which are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.
Figure 4:

Cardiac voltage-gated potassium channel (KV4.3) and its typical gain-of-function or loss-of function KCND3 mutations. (A) Schematic representation of I to corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) Schematic of KV4.3 α subunit structure and some typical GOF and LOF mutations [58], [59], [60], [61]. KV4.3 comprises four α subunits which are heterotetramers and interacting auxiliary subunits. Each α subunit consists of six segments (S1-S6) which are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.

Figure 5: Cardiac voltage-gated potassium channel (KV7.1) and its typical gain-of-function or loss-of function KCNQ1 mutations. (A) Schematic representation of I ks corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) Schematic of KV7.1 α subunit structure and some typical GOF and LOF mutations [62], [63], [64], [65], [66], [67]. KV7.1 comprises four α subunits which are heterotetramers and interacting auxiliary subunits. Each α subunit consists of six segments (S1-S6) which are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.
Figure 5:

Cardiac voltage-gated potassium channel (KV7.1) and its typical gain-of-function or loss-of function KCNQ1 mutations. (A) Schematic representation of I ks corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) Schematic of KV7.1 α subunit structure and some typical GOF and LOF mutations [62], [63], [64], [65], [66], [67]. KV7.1 comprises four α subunits which are heterotetramers and interacting auxiliary subunits. Each α subunit consists of six segments (S1-S6) which are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.

Figure 6: Cardiac voltage-gated potassium channel (KV11.1) and its typical gain-of-function or loss-of function KCNH2 mutations. (A) Schematic representation of I kr corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) Schematic of KV11.1 α subunit structure and some typical GOF and LOF mutations [68], [69], [70], [71]. KV11.1 comprises four α subunits which are heterotetramers and interacting auxiliary subunits. Each α subunit consists of six segments (S1-S6) which are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.
Figure 6:

Cardiac voltage-gated potassium channel (KV11.1) and its typical gain-of-function or loss-of function KCNH2 mutations. (A) Schematic representation of I kr corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) Schematic of KV11.1 α subunit structure and some typical GOF and LOF mutations [68], [69], [70], [71]. KV11.1 comprises four α subunits which are heterotetramers and interacting auxiliary subunits. Each α subunit consists of six segments (S1-S6) which are indicated by numbered cylinders and the fourth positively charged S4 segment as the voltage sensor domain is depicted in orange. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.

KV channels provide the outward current necessary for phase 2 plateau and early phase 3 rapid repolarization of the AP. The primary cardiac KV channel α-subunits and their currents include KV4.3/KV1.4 (I to), KV7.1 (I Ks), KV11.1 (I Kr), and KV1.5 (I Kur, only in the atria [72]).

KV4.3 channels

The KV4.3 channels, encoded by the KCND3 gene, play a crucial role in regulating cardiac repolarization. GOF mutations in KCND3 gene lead to I to current increasing, which have been reported to result in BrS, early repolarization syndrome (ERS), and sudden cardiac death (SCD) [73], 74] while LOF mutations cause spinocerebellar ataxia type 19 [58] and type 22 [59] (Figure 4). Additionally, studies suggest an intricate interplay between KV4.3 and NaV1.5 channels [75], 76]. This interaction is supported by their close proximity on the cell membrane (<40 nm) [75] and the observation that overexpressing KV4.3 channels significantly reduces NaV1.5 current density and the degree of depolarization of AP [76]. Moreover, the β subunits KchIP2 and NaVβ1 can modulate the I Na/I to balance by increasing I Na and decreasing I to [75], while GOF mutations in KCNE3, the gene encoding the KV4.3 channel β subunit MiRP2, are also associated with BrS [77]. In addition, KV4.2 and KV1.4 are also involved in the formation of I to, and typical GOF S447R mutation of KCND2 encoding KV4.2 causes autosomal dominant early-onset nocturnal paroxysmal AF while the LOF W362F mutation prolongs the APD in mouse atrial myocytes in vitro [78], 79].

KV7.1 channels

Dysfunctions of the KV7.1 channels are implicated in various cardiac diseases [80]. LOF mutations in KCNQ1 and KCNE1 genes, which encode KV7.1 channel and its auxiliary subunit respectively, cause KV7.1 channels dysfunction or restrict protein kinase A (PKA) activation of the channels [81]. These result in reduced I Ks and trigger long QT syndrome 1 (LQT1). Conversely, GOF mutations in KCNQ1 gene accelerate KV7.1 channels activation or slow channels inactivation, enhancing I Ks and associating with short QT syndrome 2 (SQT2) [80] (Figure 5).

KV11.1 channels

The KV11.1 channels are encoded by KCNH2 gene (human ether-à-go-go-related gene, hERG). LOF mutations in KV11.1, associated with long QT syndrome 2 (LQT2) [68], 82], perhaps conduce reduction of protein folding efficiency and increase retention in the endoplasmic reticulum that disrupts KV11.1 channel trafficking [68], 82]. Conversely, GOF mutations are linked to sudden death associated with short-QT syndrome [69] (Figure 6). Furthermore, LOF mutations in KCNE2 gene encoding its β subunit MiRP1 heighten the channel inactivation and induce long QT syndrome 6 (LQT6), a rare type of LQT. The KV11.1 channels are also well known for its association with drug cardiotoxicity, inhibition of which is the foremost mechanism responsible for torsades de pointes and QT prolongation that led to the withdrawal of many non-cardiovascular drugs and hERG assays have been mandated to evaluate potential proarrhythmic risk of new drugs since 2005 [83].

KV1.5 channels

KV1.5 channels are the gene products of KCNA5 which are responsible for the ultra-rapid delayed-rectifier current (I Kur) characterized by the rapid depolarization and sluggish inactivation [84]. The I Kur is almost exclusively in atrial myocytes and plays a critical role in repolarization of atrial AP. LOF mutations in KCNA5 gene are characterized by reduced I Kur, thus most prolong atrial AP duration and induce early after depolarizations [85], 86]. These LOF mutations have been identified in multiple familial AF patients. In addition, P91L and E33V mutations [87] in KCNA5 gene which are observed in LQT and SCD cases do not affect the expression or gating of KV1.5 channels, leaving the exact pathogenic mechanism unclear.

The modernized classification of clinical Class III agents includes wide ranges of nonselective and selective voltage-dependent potassium channel blockers (Class IIIa, Table 4), as well as drugs opening metabolically dependent potassium channel (Kir6.2, Class IIIb), investigational drugs blocking transmitter-dependent potassium channel (GIRK1/GIRK4, Class IIIc).

Table 4:

Class IIIa antiarrhythmic drugs [9], 12].

Class Drug exemplars Pharmacological targets Therapeutic action Clinical indications
IIIa Ambasilide Nonselective K+ channel blockers Blocks multiple K+ channel; prolongs AP recovery, ERP and QT intervals; diminishes repolarization reserve Ventricular tachycardia (without structural heart disease or with remote myocardial infarction); tachyarrhythmias with Wolff–Parkinson–White syndrome; atrial fibrillation with atrioventricular conduction via accessory pathway; ventricular fibrillation; premature ventricular contraction; tachyarrhythmias associated with supraventricular arrhythmias and atrial fibrillation
Amiodarone
Dronedarone
Ibutilide Selective KV11.1 (hERG) channel blockers Reduces I Kr; prolongs AP recovery, ERP and QT intervals; diminishes repolarization reserve Ventricular tachycardia (without structural heart disease or with remote myocardial infarction); tachyarrhythmias with Wolff–Parkinson–White syndrome; atrial fibrillation with atrioventricular conduction via accessory pathway; ventricular fibrillation; premature ventricular contraction; tachyarrhythmias associated with supraventricular arrhythmias and atrial fibrillation
Sotalol
Vernakalant Selective KV1.5 channel blockers Reduces I Kur; prolongs atrial AP recovery, ERP and QT intervals; diminishes atrial repolarization reserve Immediate conversion of atrial fibrillation

Besides, the original Class Ia antiarrhythmic drug quinidine has been suggested that its clinical antiarrhythmic effects in BrS perhaps not only include inhibition of I Na but also I to [88].

Inwardly rectifying potassium channels

The cardiac potassium channel landscape extends beyond voltage-gated potassium channels, encompassing a diverse array of inward rectifying potassium (Kir) channels that play equally crucial roles in regulating cardiac function. Kir channels conduct I K1 current at hyperpolarized membrane potentials (MP), contributing in repolarization during phases 3 and 4 of AP and stabilization of resting MP.

Kir channels are characterized by their unique inward rectification property, exhibiting a greater conductance for inward potassium currents compared to outward currents. Unlike KV channels that open and close in response to changes in membrane potential, Kir channels are constitutively active and their conductance is modulated by various factors, including intracellular signaling molecules and second messengers. This rectification arises from voltage-dependent blockade of the channel pore by intracellular magnesium ions and polyamines that occlude the channels pore and reduce outward I K1 current at positive MP [72], 89]. Besides, phosphatidylinositol (4, 5)-bisphosphate (PIP2) can activate Kir channels.

Kir2.1, encoded by the KCNJ2 gene, is the predominant Kir channel subtype in the heart. Each α subunit comprises two transmembrane segments (M1 and M2) and assembles into functional tetramers [89] (Figure 7B).

Figure 7: Cardiac inwardly rectifying potassium channel (Kir2.1) and its typical gain-of-function or loss-of function KCNJ2 mutations. (A) Schematic representation of I k1 corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) Schematic of Kir2.1 protein structure and some typical GOF and LOF mutations [90], [91], [92], [93], [94], [95], [96], [97]. Kir2.1 are functional tetramers consisting of two membrane-spanning domains (M1 and M2). The p-loop forms the ion selectivity filter. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.
Figure 7:

Cardiac inwardly rectifying potassium channel (Kir2.1) and its typical gain-of-function or loss-of function KCNJ2 mutations. (A) Schematic representation of I k1 corresponding to WT (in black, upper), gain-of function mutations (in blue, upper) and loss-of-function mutations (in red, upper) and their related ventricular AP (lower). (B) Schematic of Kir2.1 protein structure and some typical GOF and LOF mutations [90], [91], [92], [93], [94], [95], [96], [97]. Kir2.1 are functional tetramers consisting of two membrane-spanning domains (M1 and M2). The p-loop forms the ion selectivity filter. The locations of the GOF mutations are shown in green circle while the locations of LOF mutations are shown in orange rhombus.

Most LOF mutations in KCNJ2 genes induce Andersen-Tawil syndrome (ATS) which is associated with type 7 long QT syndrome (LQT7), skeletal abnormalities, and periodic paralysis [98]. These arise from dysfunctional Kir2.1 subunits encoded by LOF mutant KCNJ2 genes, leading to the formation of nonfunctional Kir channels and reduced I K1. Conversely, GOF mutations have been associated with short QT syndrome 3 (SQT3) [99] (Figure 7).

Potent blockers of Kir2 channels are rare currently, while nonselective potassium channel blockers in Class IIIa antiarrhythmic drugs exert inhibitory effects on Kir channels. Additionally, Class IIIb antiarrhythmic drugs, nicardipine and pinacidil, act as openers of Kir6.2 channels and are used in the treatment of angina pectoris.

Conclusions

Cardiac ion channels, act as gatekeepers, selectively permitting the passage of ions, thereby governing the cardiac AP and maintaining the delicate balance of cardiac rhythm. Dysfunction in these channels invariably leads to various arrhythmias.

This review has delved into the realm of arrhythmogenic ion channels in ventricular myocytes, exploring their corresponding currents in shaping the different phases of the AP and their involvement in the pathogenesis of cardiac arrhythmias. We provide an overview of the predominant subtype of NaV, CaV, KV, and Kir channels, along with the diverse antiarrhythmic drugs that targeting cardiac ion channels based on the updated Singh-Vaughan Williams classification system which categorized antiarrhythmic drugs according to their primary mechanism of action on ion channels. In addition, some other channels that are not mentioned in detail are involved in the physiologic activity of the cardiac AP. For example, the hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels mediate a mixed sodium/potassium inward I f current which is responsible for the early part of the diastolic depolarization in the SAN, and dysfunctional HCN4 channels might directly cause rhythm disorders which can be treated with ivabradine as a new approach in selective HR reduction [100], 101].

However, the quest for more effective and targeted antiarrhythmic therapies continues. Traditional medications do not provide complete protection and can have serious side effects while Ablation techniques are also tissue-breaking and invasive. Device therapy like pacemakers have a limited range of indications, and patients can get infections when devices are implanted and in the long term there are also risks such as device failure [102]. Research into novel therapeutic strategies, such as gene therapy and small molecule modulators, holds great promise for the future management of cardiac arrhythmias. For instance, there are six fundamental strategies for gene and cell therapy: gene transfer, allele-specific silencing, gene editing, modulation of signal pathways, differentiation of stem cells, and hybrid gene-gene/cell, which is therapeutic approaches of introducing specific genetic material into cells or directly replacing dysfunctional cells with healthy cells to correct the underlying case of disease [102]. Furthermore, advancements in computational modeling and structural biology will pave the way for the development of personalized antiarrhythmic therapies, minimizing side effects. The high-resolution structure of the cardiac channels can give detailed insights into voltage-dependent activation, ion selectivity, arrhythmia mechanisms, and antiarrhythmic drug action at the atomic level, such as a pathogenic gating pore ∼2 Å in diameter created by an arrhythmia mutation of SCN5A(9), the same conformation of CaV1.2 that is bound by calciseptin [54], amiodarone and dihydropyridine drugs, the unique properties of the central cavity of the hERG channel which likely contribute to hERG block by many drugs [103] and so on [89], 104].

Corresponding authors: Yang Yang, Borch Department of Medicinal Chemistry and Molecular Pharmacology (MCMP), Purdue University College of Pharmacy, West Lafayette, IN, USA; and Purdue Institute for Integrative Neuroscience (PIIN), West Lafayette, IN, USA, E-mail: ; and Zhuo Huang, State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China; and IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China, E-mail:
Shiqi Liu and Wei Wang contributed equally to this study.

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author Contribution: Zhuo Huang: Conceptualization, Writing – review and editing, Supervision. Yang Yang: Writing – review and editing, Supervision. Shiqi Liu: Writing – original draft, review and editing, Visualization. Wei Wang: Writing – original draft, review and editing. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: No conflicts of interest, financial or otherwise, are declared by the authors.

  6. Research funding: None declared.

  7. Data availability: Not applicable.

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Received: 2024-10-19
Accepted: 2025-02-05
Published Online: 2025-03-03

© 2025 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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https://doi.org/10.1515/mr-2024-0085
Schlagwörter für diesen Artikel
ion channels; action potential; arrhythmias; antiarrhythmic drugs
Creative Commons
BY-NC-ND 4.0

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Immune cells in Alzheimer’s disease: insights into pathogenesis and potential therapeutic targets
  4. Selenium compounds for cancer prevention and therapy – human clinical trial considerations
  5. Ventricular ion channels and arrhythmias: an overview of physiology, pathophysiology and pharmacology
  6. Yoga and chronic diseases: an umbrella review of systematic reviews and meta-analyses
  7. Perspectives
  8. Histone lactylation as a driver of metabolic reprogramming and immune evasion
  9. From tumor immunity to precision medicine: the next step in B7-H3/CD276 research
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