What Are hERG Channels and Why Are They Important?

A cell’s membrane contains specialized gates that manage the flow of electrical signals. One particular gate, the human Ether-à-go-go-Related Gene (hERG) channel, is a specific type of potassium ion channel. Found primarily in the muscle cells of the heart, its correct operation is fundamental to maintaining a normal, steady heartbeat. The hERG channel’s role in cardiac function places it at the center of both inherited heart conditions and modern pharmaceutical safety evaluations.

The Biological Role of hERG Channels

The hERG channel is a complex protein structure that creates a passageway through the membrane of heart muscle cells, known as cardiac myocytes. This channel is highly selective, specifically allowing positively charged potassium ions (K+) to move out of the cell. The genetic instructions for constructing this protein are encoded in a gene named KCNH2. While predominantly associated with the heart, these channels are also present in other tissues, including neurons and smooth muscle.

The channel itself is composed of four identical alpha subunits that assemble to form the central pore. This intricate structure is not static; it is influenced by various cellular signals that can regulate the channel’s activity, for instance by causing the cell to pull the channel inward from the surface.

Regulating the Heart’s Electrical Cycle

The rhythmic contraction of the heart is driven by a carefully controlled electrical wave called an action potential. This process involves depolarization (contraction) and repolarization, a “recharging” period that prepares the cell for the next beat. The hERG channel’s primary function occurs during this repolarization phase, acting like the reset of a metronome to ensure precise timing.

During repolarization, the hERG channel opens, allowing potassium ions to flow out of the cardiac myocyte. This outward movement of positive charge restores the cell to its resting electrical state. The current generated by this ion flow is known as the rapid delayed rectifier current (IKr), and it is a component of the cardiac action potential. This process ensures the heart has just enough time to refill with blood before the next contraction.

The precise opening and closing of the hERG channel dictates the length of the action potential. This duration is directly linked to the QT interval seen on an electrocardiogram (ECG), a common diagnostic tool used to measure the heart’s electrical activity.

Long QT Syndrome and hERG Channels

When the repolarization process is delayed, it leads to a condition known as Long QT Syndrome (LQTS), where the heart muscle takes an extended amount of time to recharge between beats. This delay creates an unstable electrical environment, elevating the risk of dangerous heart rhythms like Torsades de Pointes. Malfunctions in the hERG channel are a primary cause of this syndrome.

LQTS related to hERG channels arises from two distinct causes. One is genetic, resulting from mutations in the KCNH2 gene. This inherited form, called Congenital LQTS Type 2, means the channels are built incorrectly from birth, impairing their function.

The second cause is acquired, where the hERG channel protein is normal but its function is blocked by an external substance, most often a medication. This is a known side effect of several drug classes that bind to the hERG channel and obstruct the flow of potassium ions, including:

• Antibiotics
• Antifungals
• Antihistamines
• Antipsychotic medications

The channel’s structure, with a large inner vestibule, makes it particularly susceptible to blockage.

Importance in Pharmaceutical Safety

The propensity for medications to inadvertently block hERG channels has significant implications for drug development and public health. Because such a blockage can lead to acquired LQTS and potentially life-threatening arrhythmias, assessing a new drug’s effect on the hERG channel has become a standard part of safety pharmacology.

Regulatory agencies worldwide mandate that new drug candidates undergo hERG screening assays early in the development process, before they are administered to humans. These tests measure how strongly a drug binds to and inhibits the hERG potassium channel. A compound’s tendency to block these channels is a frequent reason for its failure during development.

This rigorous screening has prevented many potentially dangerous drugs from reaching the market. In some instances, drugs already in use have been withdrawn after their hERG-blocking properties were identified. The focus on hERG liability has shaped modern drug discovery, forcing scientists to design molecules that are effective for their intended purpose but free from this cardiac side effect.