The ERG1 K+ Channel and Its Role in Neuronal Health and Disease

Abstract

The ERG1 potassium channel, encoded by KCNH2, has long been associated with cardiac electrical excitability. Yet, a growing body of work suggests that ERG1 mediates physiology throughout the human body, including the brain. ERG1 is a regulator of neuronal excitability, ERG1 variants are associated with neuronal diseases (e.g., epilepsy and schizophrenia), and ERG1 serves as a potential therapeutic target for neuronal pathophysiology. This review summarizes the current state-of-the-field regarding the ERG1 channel structure and function, ERG1’s relationship to the mammalian brain and highlights key questions that have yet to be answered.

Key role for Kv11.1 (ether‐a‐go‐go related gene) channels in rat bladder contractility

“…However, this does not rule out that E4031 may also be affecting urothelial, interstitial cells, or neuronal depolarization and remains to be further investigated in future studies. Of note, Kv11.1 channels have been identified in neurons and they are involved in mediating the neuronal resting current (e.g., Sanchez‐Conde et al, 2022 ).…”

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review

“…Unique current profile of the ERG channels contributes to regulation of neuronal action potential firing frequency, spike frequency adaptation, and resting membrane potential. 31 ERG potassium channels expressed in various tissues, many of which are linked to disease. 32 ERG potassium channels are also widely expressed in the brain, where they contribute to regulating the frequency and discharge stability of neurons.…”

“…Upon repolarization, ERG channels quickly recover from the inactivated state but, owing to the slow deactivation time course, remain in a conductive state and diminish electrical activity during prolonged stimuli. Unique current profile of the ERG channels contributes to regulation of neuronal action potential firing frequency, spike frequency adaptation, and resting membrane potential 31 . ERG potassium channels expressed in various tissues, many of which are linked to disease 32 .…”

It is premature for a unified hypothesis of sudden unexpected death in epilepsy: A great amount of research is still needed to understand the multisystem cascade

“…43 Variants in cardiac ion channel genes KCNH2, KCNQ1, and SCN5A traditionally linked to congenital long QT syndrome are also associated with epilepsy and SUDEP. 41,[43][44][45][46][47][48][49] KCNA1, which encodes K v 1.1 potassium channels with predominantly brain-specific expression, can influence cardiac function through autonomic effects. 50 In a genetic mouse model of Dravet syndrome, mScn1a haploinsufficiency paradoxically led to increased cardiac Na + current, cardiomyocyte action potential prolongation, myocyte hyperexcitability, re-excitation, increased QT c duration, nonsinus beats, and re-entrant arrhythmias.…”

“…Fifteen percent of SUDEP cases have variants in genes linked to cardiac arrhythmias 43 . Variants in cardiac ion channel genes KCNH2 , KCNQ1 , and SCN5A traditionally linked to congenital long QT syndrome are also associated with epilepsy and SUDEP 41,43–49 . KCNA1 , which encodes K v 1.1 potassium channels with predominantly brain‐specific expression, can influence cardiac function through autonomic effects 50 …”