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**171**

**Chapter 10**

**Abstract**

epilepsy

**1. Introduction**

encoding VGIC predominate [2].

novel physiological principles [2].

Ion Channels in Epilepsy:

Hyperexcitability

potential targets for the precise treatment of epilepsy.

Blasting Fuse for Neuronal

*Shuzhang Zhang, Yudan Zhu, Jiwei Cheng and Jie Tao*

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

**Keywords:** ion channels, VGSCs, Kv channels, Cav channels, TRPs, mutation,

Epilepsy is one of the chronic brain disorders characterized by recurrent seizures due to abnormal excessive electrical discharges of cerebral neurons [1]. It is believed that genetic factors play a crucial role in the etiopathogenesis of epilepsy. So far ~1000 genes have been proved to be associated with epilepsy, among which genes

VGICs are pore-forming membrane proteins. Their functions include establishing APs and maintaining homeostasis by gating the ionic flow traversing the cell membrane, managing the ionic flow across cells and regulating Ca2+ signal transduction, which are essential to the neuroexcitability, so VGICs are potentially involved in epileptogenesis [2]. The association of VGIC genes and epilepsy might provide insights into the etiopathogenesis underlying epilepsy. Pathophysiological studies illuminated that two key defects are (i) a neuronal disinhibition induced by loss-of-function of VGIC gene expressed specifically in inhibitory interneurons (for example, Nav1.1 and P/Q VGCCs) or (ii) dysfunction of axon initial segments, the neuronal structure in which APs are generated and many VGICs (such as Nav1.2 and Kv7) are mainly localized (**Figure 1**). Moreover, clinically originated studies identified novel genes, defined their neuronal functions, and sometimes established
