Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability

Abstract

Voltage-gated ion channels (VGICs), extensively distributed in the central nervous system (CNS), are responsible for the generation as well as modulation of neuroexcitability and considered as vital players in the pathogenesis of human epilepsy, with regulating the shape and duration of action potentials (APs). For instance, genetic alterations or abnormal expression of voltage-gated sodium channels (VGSCs), Kv channels, and voltage-gated calcium channels (VGCCs) are proved to be associated with epileptogenesis. This chapter aims to highlight recent discoveries on the mutations in VGIC genes and dysfunction of VGICs in epilepsy, especially focusing on the pathophysiological and pharmacological properties. Understanding the role of epilepsy-associated VGICs might not only contribute to clarify the mechanism of epileptogenesis and genetic modifiers but also provide potential targets for the precise treatment of epilepsy.

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients

“…Ion channel dysfunction, either caused by mutations or acquired, has been associated with epilepsy. Many AEDs tend to manipulate the ion permeability of these channels to modify neuronal excitability [ 78 ]. In the present study, we have demonstrated the up-regulation of AQP1, KCNK10, KCNH8, P2RX7, SGK1, SGK2, SLC12A2, SLC6A2, SLC44A1, SLC45A3, SCLC5A11, SCL26A9, CLCA4 and SEPT4 in MAX of FCD type II patients.…”

“…Increased expression of SLC12A2 has been reported in surgically resected tissue specimens from FCD patients [ 85 ]. SLC26A9 , a highly selective chloride ion channel, CLCA4 , calcium sensitive chloride channel, SLC45A3 , SLC5A11 may be involved in ion transport and neurotransmitter release in FCD [ 78 ]. SLC44A1, a choline transporter, may contribute to membrane synthesis and myelin production.…”

Neurotoxic and convulsant effects induced by jack bean ureases on the mammalian nervous system

“…Voltage gated sodium channels (VGSC) are often a therapeutic target for epilepsies (Mantegazza et al 2010). The Nav1.1 is present primarily in inhibitory gabaergic neurons (Zhang et al 2019). Mutations causing loss of function of Nav 1.1 can induce severe untreatable epilepsies (Mantegazza et al 2005).…”

“…Mutations causing loss of function of Nav 1.1 can induce severe untreatable epilepsies (Mantegazza et al 2005). If Nav1.1 currents are blocked, the inhibition in a given neural network is reduced because of impaired gabaergic signaling, so that excitatory neurons would fire excessively causing seizures (Zhang et al 2019). It has been demonstrated a striking relationship between the neuronal Nav 1.6 and spike wave discharges, the hallmark of epilepsy crises (Papale et al 2009).…”

Transcriptional Regulation of Channelopathies in Genetic and Acquired Epilepsies

“…In addition, also deletions and duplications of (part of) the gene can strongly affect normal channel function (Borlot et al, 2017;Monlong et al, 2018). Since the focus of this review is on the transcriptional regulation of ion channels, listing all genetic variants within the coding regions of ion channel genes is beyond the scope of this article (for reviews, see Deng et al, 2014;Wei et al, 2017;Zhang et al, 2019).…”