Potassium Channels in Epilepsy

Abstract

This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dynamic, aggravating, or adaptive transcriptional and posttranslational alterations. In these cases, it often remains elusive whether the alteration is causal or merely incidental. With ∼80 potassium channel types, of which ∼10% are known to be associated with epilepsies (in humans) or a seizure phenotype (in animals), if genetically mutated, a comprehensive review is a challenging endeavor. This goal may seem all the more ambitious once the data on posttranslational alterations, found both in human tissue from epilepsy patients and in chronic or acute animal models, are included. We therefore summarize the literature, and expand only on key findings, particularly regarding functional alterations found in patient brain tissue and chronic animal models.

Figure 1.

Tree of mammalian potassium channel subunits and epilepsy research hot spots. The figure shows the known potassium (K) channel α subunits families and epilepsy research hot spots. Their relation is grouped according to sequence similarities in three major groups: two, four, and six transmembrane (TM) domain channels (2TM, 4TM, and 6TM, respectively), which are synonymously named according to gross functional differences as: inward rectifier K (K_ir), two-pore domain leak K (K_2P), and voltage-gated K (K_v) channels, respectively. Hypothetical (not realistic for individual members) main characteristics of the respective current/voltage relationships are plotted in insets as blue lines. Following the functional name, is the human genome organization (HUGO) name. Numbers in parenthesis are PubMed search results for “(HUGO AND epilepsy) AND Humans[Filter] NOT Review[Filter].” Marked in red are those subunits that yielded more than 10 results in this PubMed search.

Figure 2.

Possible mechanisms of the main genetic potassium channel defects found in epilepsy patients. The cartoon illustrates the localization and effect of loss-of-function (↓) or gain-of-function (↑) mutations of K_v7.2/7.3 (KCNQ channels), K_v1.2, BK (K_Ca1.1), K_v3.1, and K_v4.1. Normal conditions are symbolized by black traces, functional changes caused by mutations in red. K_v7.2/7.3 channels are mainly located on axons and axon-initial segments of neurons, and are usually active at resting membrane potential, thereby governing excitability at the axon hillock. A loss-of-function mutation should result in both accentuated excitatory postsynaptic potentials (EPSPs) as well as in increased action potential firing, which would readily explain hyperexcitability—however, does not explain the association with either relatively benign syndromes like benign familial nocturnal convulsion (BNFC), or relatively severe syndromes like Ohthara syndrome. In a similar way, a loss-of-function mutation of K_v1.2, also expressed on the axon hillock, but constituting a delayed rectifier channel not constitutively open at rest, will likely increase action potential firing frequency, again accounting for increased hyperexcitability. The gain-of-function mutations also described in patients, however, remain difficult to explain mechanistically (?). This also applies for BK (K_Ca1.1) channel defects, in which gain-of-function alterations do not readily conjure a mechanism (?). Mutations of K_v3.1, in turn, could elicit an overall increase in excitability, as these channels are expressed mainly on interneurons and convey, by virtue of their fast hyperpolarizing action, fast-firing properties to them. Should these fail, interneurons are expected to fire less intensively. Last, mutations of K_ir4.1 have been described. As these are expressed on astrocytes and are responsible for uptake of potassium (spatial buffering), a loss of function should result in decreased spatial buffering and, hence, activity-dependent pathological accumulation of K⁺ with an overall excitatory effect by depolarizing neighboring cells.