Kcnh2Edit
Kcnh2, often written as KCNH2, refers to a gene encoding a voltage-gated potassium channel that plays a central role in cardiovascular electrophysiology. The protein product is a member of the ether-à-go-go (EAG) family of potassium channels and contributes to the IKr current that helps terminate the cardiac action potential. In humans, the canonical symbol for the gene is KCNH2, and the encoded channel is commonly referred to as the hERG (human Ether-à-go-go-Related Gene) channel. The term Kcnh2 is sometimes encountered in older literature or when referring to closely related family members, but the KCNH2/hERG designation is the standard in modern genetics and physiology.
Understanding KCNH2 is essential for grasping how the heart maintains a reliable rhythm and how disturbances in this system can lead to dangerous arrhythmias. Beyond the heart, related channels in the same family participate in electrical signaling in other tissues, illustrating how a single gene can impact multiple organ systems. The study of KCNH2 thus sits at the intersection of molecular biology, physiology, and clinical medicine, and it features prominently in discussions about drug safety and precision medicine.
Overview
KCNH2 encodes a subunit of a voltage-gated potassium channel that forms tetrameric complexes. Each subunit contributes to the pore and the gating machinery that opens or closes the channel in response to changes in membrane potential. The hERG channel conducts the IKr current, which activates during the repolarization phase of the cardiac action potential and helps reset the electrical state of heart muscle between beats. The channel’s distinctive gating properties give the heart a narrow and predictable repolarization window, which is essential for maintaining a regular heart rate.
The protein is a member of the broader family of voltage-gated potassium channels, and its family relationships connect it to other channels that share structural motifs and regulatory mechanisms. Researchers frequently discuss KCNH2 alongside other cardiac ion channels, such as those responsible for the IKs current or the inward rectifier currents, to explain how the heart balances depolarizing and repolarizing forces.
Key terms to connect with include voltage-gated potassium channel and ion channel, which anchor the discussion in the general principles of excitability and electrical signaling. The hERG family is also discussed in relation to cardiac action potential and the specific phases of repolarization that hinge on IKr.
Structure and expression
KCNH2 encodes the pore-forming alpha subunit of the hERG channel. The protein assembles as a tetramer and comprises six transmembrane segments (S1–S6) per subunit, with the S4 segment acting as a voltage sensor and the S5–S6 region forming the pore. The cytoplasmic N- and C-termini regulate trafficking, gating, and interactions with auxiliary proteins. The channel’s rapid activation and deactivation kinetics give it a unique role in shaping the late phase of repolarization.
Expression of KCNH2 is highest in cardiac tissue, particularly in ventricular myocardium and Purkinje fibers, where IKr is a major contributor to action potential repolarization. Expression is also detected in other tissues, including certain regions of the brain, reflecting the broader roles of related channels in excitability, though the cardiac function is the most clinically salient aspect for this gene.
For readers exploring the molecular context, links to tetramer structure, S1–S6 transmembrane segments, and pore loop architecture help connect function to form. See also discussions of the hERG channel and its pharmacology.
Physiological role
The IKr current, produced by the hERG channel, is a central driver of cardiac repolarization (phase 3 of the action potential). It provides a rapid repolarizing current that helps terminate the action potential and sets the duration of the cardiac cycle. The interplay between IKr and other currents, such as IKs, underpins the heart’s repolarization reserve—a concept describing the heart’s ability to adapt electrical recovery when one pathway is compromised.
Because of its gating kinetics and drug sensitivity, KCNH2 is a focal point in discussions of how various substances influence cardiac rhythm. Changes in channel function can alter repolarization timing, which in turn affects the QT interval on the electrocardiogram. This has led researchers to examine how genetic variation in KCNH2 or pharmacologic blockade of the channel can predispose individuals to arrhythmias.
Connections to broader topics include cardiac electrophysiology, action potential, and I_Kr as part of the network of currents that determine rhythm regularity.
Clinical significance
Mutations in KCNH2 are associated with heritable arrhythmia syndromes, most notably Long QT Syndrome type 2 (LQTS2). LQTS2 increases the risk of abnormal repolarization, torsades de pointes, and, in severe cases, sudden cardiac death. The clinical presentation can range from asymptomatic electrocardiographic findings to syncope or sustained arrhythmias, particularly under stress or with concomitant medications that influence repolarization.
Beyond monogenic disease, pharmacologic blockade of the hERG channel is a well-recognized cause of acquired QT prolongation. A broad spectrum of drugs—ranging from antiarrhythmics to non-cardiac medications—can bind to hERG and reduce IKr, prolonging the QT interval and potentially triggering torsades de pointes in susceptible individuals. This has driven regulatory emphasis on hERG screening during drug development and post-market surveillance, and it has influenced clinical practice in terms of monitoring patients started on drugs with known hERG-blocking potential.
Key concepts include Long QT syndrome, LQTS type 2, torsades de pointes, and drug-induced QT prolongation. The relationship between genotype (KCNH2 variants) and phenotype (arrhythmic risk) continues to inform debates about genetic testing, risk stratification, and personalized medicine.
Regulation and pharmacology
Because hERG blockade can have serious consequences, there is a strong pharmacological and regulatory emphasis on understanding how drugs interact with the KCNH2 channel. The channel’s drug-binding properties are a central concern in early-stage screening to identify compounds with unacceptable proarrhythmic risk. This has shaped pharmaceutical research, encouraging alternative pathways and safer designs to avoid unintended IKr inhibition.
Scientists also study how trafficking defects, trafficking rescue, and cellular context influence channel function. These investigations help explain why some mutations cause disease not only by altering gating but also by reducing cell surface expression of the channel. The clinical implications connect to genetic testing for inherited risk and to broader questions about how best to balance patient safety with therapeutic innovation.
Research and controversies
Ongoing research explores how KCNH2 variants alter channel function, how auxiliary proteins modulate IKr, and how this translates into patient risk. A central debate in pharmacology centers on how best to screen for hERG liability without unnecessarily constraining drug discovery. Some researchers advocate in-depth, mechanism-based assessments that capture trafficking defects and channel–protein interactions, while others emphasize high-throughput strategies to identify glaring liabilities early, with post-market surveillance to catch rare adverse events.
Another area of discussion concerns the relative contributions of genetics and environment to arrhythmic risk in individuals with KCNH2 variants. Clinically, this translates into discussions about when to pursue genetic testing, how to interpret variants of uncertain significance, and how to craft personalized management strategies that consider both genotype and lifestyle factors.
See also entries on the broader framework of cardiac electrophysiology and safety regulation, including ion channel regulation, pharmacology, and cardiac arrhythmia.