Mining the Virgin Land of Neurotoxicology: A Novel Paradigm of Neurotoxic Peptides Action on Glycosylated Voltage-Gated Sodium Channels

Zhirui Liu,Jie Tao,Pin Ye,Yonghua Ji

doi:10.1155/2012/843787

Abstract

Voltage-gated sodium channels (VGSCs) are important membrane protein carrying on the molecular basis for action potentials (AP) in neuronal firings. Even though the structure-function studies were the most pursued spots, the posttranslation modification processes, such as glycosylation, phosphorylation, and alternative splicing associating with channel functions captured less eyesights. The accumulative research suggested an interaction between the sialic acids chains and ion-permeable pores, giving rise to subtle but significant impacts on channel gating. Sodium channel-specific neurotoxic toxins, a family of long-chain polypeptides originated from venomous animals, are found to potentially share the binding sites adjacent to glycosylated region on VGSCs. Thus, an interaction between toxin and glycosylated VGSC might hopefully join the campaign to approach the role of glycosylation in modulating VGSCs-involved neuronal network activity. This paper will cover the state-of-the-art advances of researches on glycosylation-mediated VGSCs function and the possible underlying mechanisms of interactions between toxin and glycosylated VGSCs, which may therefore, fulfill the knowledge in identifying the pharmacological targets and therapeutic values of VGSCs.

Highlights

In neurons and most excitable cells, multiform action potentials driven by depolarizing neuronal firing are considered to be accounted by spatiotemporal activation and integral performances of tissue-specific Voltage-gated sodium channels (VGSCs) [1]
The most common form of glycosylation sites on VGSCs protein is mainly composed by N-linked sialic acids, [8]
For the reason that the external surface of one VGSC α-subunit was estimated to have about 110–130 negative charges composed by the sialic acids [32], it is likely that sialic acid alters the electric field sensed by the gating mechanism of the channel [10]

Summary

Introduction

In neurons and most excitable cells, multiform action potentials driven by depolarizing neuronal firing are considered to be accounted by spatiotemporal activation and integral performances of tissue-specific VGSCs [1]. The hairpin-like loop between S5 and S6 segments region is functioned as ion-permeable pore [2] Both α and β subunits are highly glycosylated cross-membrane proteins [3,4,5,6,7] (Figure 1). To address the above problems, one may resort to segment-swap chimera construction or glycosylationdeficient cells to reduce the level of glycosylation [10, 22]. The pharmacological studies have demonstrated that the binding of these toxins and their targets is highly subtype specific [26, 27, 29] They are hopefully utilized as efficient tools to more precisely uncover the role of glycosylation on VGSCs gating and the overall performances on channel pathology in clinical therapy

Mechanism of Glycosylation to the Voltage Dependence of VGSCs Gating

Novel Paradigm of Interaction between VGSCs and Neurotoxic Peptides

Findings

Perspectives