The human Ether-à-go-go-Related Gene, or hERG, is a protein channel that plays a significant role in the electrical system of the heart. This channel is responsible for managing the flow of charged particles across cardiac cell membranes, a process that dictates the rhythm of every heartbeat. When this channel malfunctions, either due to genetic changes or outside interference, the electrical stability of the heart can be compromised, leading to potentially serious consequences. Because of its sensitivity to a wide range of chemical compounds, hERG has become a primary focus in the development and safety testing of nearly all new medications.
What Are hERG Channels and Where Are They Found?
The hERG channel is a voltage-gated potassium ion channel, acting as a selective pore embedded in the cell membrane. Its official designation is Kv11.1, and it is encoded by the \(KCNH2\) gene. hERG controls the passage of positively charged potassium ions (\(K^+\)), allowing them to flow out of the cell. This outward flow of charge is fundamental to electrical signaling.
The channel structure is formed by the assembly of four identical protein subunits, each containing six segments that span the cell membrane. While hERG proteins are present in many tissues, including the brain, smooth muscle, and endocrine cells, their primary role is in the heart. In cardiac myocytes, these channels are positioned to regulate the timing of the heart’s electrical cycle.
Maintaining the Heartbeat: The Function of hERG
The primary function of hERG is to facilitate repolarization, which is the electrical reset of the cardiac cell after a contraction. Each heartbeat is initiated by an electrical signal, the action potential. The hERG channel mediates the rapid component of the delayed rectifier potassium current, often called \(I_{Kr}\).
This current acts like an electrical brake, helping to bring the cell’s membrane potential back to its resting state to prepare for the next beat. The hERG channel has a unique gating mechanism. Although the channel opens during the initial depolarization, it quickly enters an inactivated state, limiting the potassium current during the plateau phase.
As the cell begins to repolarize, the channel quickly recovers from inactivation and briefly reopens before closing completely. This precise timing creates a surge of outward potassium current, effectively shortening the duration of the action potential. If repolarization is delayed, the electrical signal remains active for too long, which can lead to serious arrhythmias.
The Link Between hERG and Medication Safety
The hERG channel’s structure possesses a unique binding pocket that makes it susceptible to interference from a broad array of chemical compounds. This promiscuity means that many non-cardiac drugs—including common antibiotics, antihistamines, antipsychotics, and antidepressants—can inadvertently bind to and block the hERG channel. Blocking the channel reduces the outward \(I_{Kr}\) current, which directly impedes the heart cell’s ability to repolarize efficiently.
The physiological consequence of hERG channel blockade is a lengthening of the cardiac action potential, visible on an electrocardiogram (ECG) as a prolonged QT interval. This condition is known as acquired Long QT Syndrome (aLQTS) and is a significant cardiac safety concern in pharmacology. A prolonged QT interval destabilizes the electrical environment of the heart, increasing the risk for a life-threatening arrhythmia.
The most dangerous outcome is a specific, rapid form of ventricular tachycardia known as Torsades de Pointes (TdP). This condition can rapidly degenerate into ventricular fibrillation and sudden cardiac death. Following several high-profile drug withdrawals in the 1990s due to hERG-related cardiac toxicity, regulatory bodies now require mandatory hERG screening for virtually all new drug candidates. This pre-clinical testing ensures that new medications are checked for their potential to block the channel.
Inherited hERG Defects: Long QT Syndrome
Beyond drug-induced effects, the hERG channel can also be compromised by inherited genetic changes. Mutations in the \(KCNH2\) gene are the cause of Type 2 Long QT Syndrome (LQTS2), a congenital heart rhythm disorder. LQTS2 is one of the most common forms of inherited Long QT Syndrome, accounting for approximately 25 percent of cases.
These genetic mutations typically result in a loss-of-function, meaning the cell produces fewer functional hERG channels or the channels do not conduct potassium ions properly. The resulting reduction in the \(I_{Kr}\) current leads to a permanent delay in cardiac repolarization. Individuals with LQTS2 have an increased risk of developing Torsades de Pointes, often triggered by emotional stress or sudden noise. Symptoms can include episodes of fainting, seizures, and sudden cardiac arrest.