K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

Abstract

K+ channels are important determinants of seizure susceptibility. These membrane proteins, encoded by more than 70 genes, make the largest group of ion channels that fine-tune the electrical activity of neuronal and non-neuronal cells in the brain. Their ubiquity and extremely high genetic and functional diversity, unmatched by any other ion channel type, place K+ channels as primary targets of genetic variations or perturbations in K+-dependent homeostasis, even in the absence of a primary channel defect. It is therefore not surprising that numerous inherited or acquired K+ channels dysfunctions have been associated with several neurologic syndromes, including epilepsy, which often generate confusion in the classification of the associated diseases. Therefore, we propose to name the K+ channels defects underlying distinct epilepsies as “K+ channelepsies,” and introduce a new nomenclature (e.g., Kx.y-channelepsy), following the widely used K+ channel classification, which could be also adopted to easily identify other channelopathies involving Na+ (e.g., Navx.y-phenotype), Ca2+ (e.g., Cavx.y-phenotype), and Cl− channels. Furthermore, we discuss novel genetic defects in K+ channels and associated proteins that underlie distinct epileptic phenotypes in humans, and analyze critically the recent progress in the neurobiology of this disease that has also been provided by investigations on valuable animal models of epilepsy. The abundant and varied lines of evidence discussed here strongly foster assessments for variations in genes encoding for K+ channels and associated proteins in patients with idiopathic epilepsy, provide new avenues for future investigations, and highlight these proteins as critical pharmacological targets.

Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms

“…From published work, both loss- and gain-of-function potassium channel mutants had been linked to epilepsy. Among them, loss-of-function of Kv1.1, Kv1.2, Kv4.2 and Kv7.1, Kv7.2 potassium channels are associated with epilepsy (Brew et al, 2007; D’Adamo et al, 2013; Smart et al, 1998; Wang et al, 2015; Zeng et al, 2015). On the other hand, gain-of-function of the BK and Slack channel mutants are also linked with Epilepsy (Barcia et al, 2012; Du et al, 2005; Yang et al, 2010).…”

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

“…Therefore, gain-of-function of Na + channels (for a comprehensive review, see Eijkelkamp et al, 2012) and/or loss-of-function of K + channels (for a comprehensive review, see D’Adamo et al, 2013) have proepileptic effects in most cases. Some examples include gain-of-function of voltage-gated Na + (Nav) channels Nav1.2/1.6 (responsible for action potential generation and propagation) (Sugawara et al, 2001), Nav1.3 (responsible for dendritic postsynaptic potentials propagation) (Estacion et al, 2010; Holland et al, 2008), and loss-of-function of voltage-gated K + (Kv) channels Kv1.1/1.2 (responsible for action potentials propagation and vesicles release) (Brew et al, 2007; Rho et al, 1999), Kv2.1/8.2 (responsible for dendritic postsynaptic potentials propagation) (Jorge et al, 2011), Kv4.2 (responsible for backpropagating action potentials in dendrites) (Barnwell et al, 2009; Bernard et al, 2004), Kv7.2/7.3 (required for repolarization of AIS) (Peters et al, 2005).…”

KCNA4deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability

“…Among the A-type channels (Kv1.4, Kv3.3, Kv3.4, Kv4.1, Kv4.2 and Kv4.3) only Kv3.3, Kv4.2 and Kv4.3 have been linked to hereditary disorders 18 19. It is noteworthy that these disorders are mostly seen in an autosomal dominant fashion 20–25.…”