Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox

Abstract

Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy and neurodevelopmental disorders, for which new genes or new variants of preexisting candidate genes are being continuously identified at increasing rates every year. A surprising finding of these efforts is the recognition that gain of function potassium channel variants are actually associated with certain types of epilepsy, such as malignant migrating partial seizures of infancy or early-onset epileptic encephalopathy. This development has been difficult to understand as traditionally potassium channel loss-of-function, not gain-of-function, has been associated with hyperexcitability disorders. In this article, we describe the current state of the field regarding the gain-of-function potassium channel variants associated with epilepsy (KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, and KCNT1) and speculate on the possible cellular mechanisms behind the development of seizures and epilepsy in these patients. Understanding how potassium channel gain-of-function leads to epilepsy will provide new insights into the inner working of neural circuits and aid in developing new therapies.

Keywords: epilepsy; gain of function; neurons; potassium channels; seizures.

Figure 1. Gain-of-function variants have been identified in multiple potassium channels

Illustration showing different potassium channels associated with epilepsy channelopathies. Red marks indicate locations of identified gain-of-function variants.

Figure 2. Kv1.2 channels regulate axonal excitability

(A) Top, blocking Kv1 channels in Layer 5 pyramidal neurons prolongs the axonal but not somatic action potential. Bottom, subthreshold depolarization inactivates Kv1 channels leading to alter action potential waveform. Reprint with permission from Kole and others (2007), with permission from Elsevier. (B) Illustration showing that Kv1.2 gain-of-funciton variants could shift activation of Kv1.2 channels at resting membrane potential leading to their inactivation and subsequent greater glutamate release.

Figure 3. KCNJ10 channels regulate neuronal excitability

(A) Left, illustration showing location of identified KCNJ10 variants in patients with epilepsy and autism. Right, examples of a KCNJ10 gain-of-function variant from a patient with epilepsy and autism. Reprint with permission from Sicca and others (2011), with permission from Elsevier. (B) Illustration showing that repetitive firing leads to build of extracellular potassium and axonal sodium channel inactivation. KCNJ10 GOF variants might prevent the potassium ion build up allowing neurons to fire in higher frequency.

Figure 4. KCNT1 gain-of-function variants lead to greater KCNT1 currents

Voltage clamp recordings of of KCNT1 variants identified in patients with epilepsy. Notice that most variants lead to several fold greater KCNT1 currents than wild-type KCNT1 responses. Reprint with permission from Kim and others (2014), with permission from Elsevier.