Abstract

Voltage sensor domains (VSDs) are a feature of voltage gated ion channels (VGICs) and voltage sensitive proteins. They are composed of four transmembrane (TM) segments (S1–S4). Currents leaking through VSDs are called omega or gating pore currents. Gating pores are caused by mutations of the highly conserved positively charged amino acids in the S4 segment that disrupt interactions between the S4 segment and the gating charge transfer center (GCTC). The GCTC separates the intracellular and extracellular water crevices. The disruption of S4–GCTC interactions allows these crevices to communicate and create a fast activating and non-inactivating alternative cation-selective permeation pathway of low conductance, or a gating pore. Gating pore currents have recently been shown to cause periodic paralysis phenotypes. There is also increasing evidence that gating pores are linked to several other familial diseases. For example, gating pores in Nav1.5 and Kv7.2 channels may underlie mixed arrhythmias associated with dilated cardiomyopathy (DCM) phenotypes and peripheral nerve hyperexcitability (PNH), respectively. There is little evidence for the existence of gating pore blockers. Moreover, it is known that a number of toxins bind to the VSD of a specific domain of Na+ channels. These toxins may thus modulate gating pore currents. This focus on the VSD motif opens up a new area of research centered on developing molecules to treat a number of cell excitability disorders such as epilepsy, cardiac arrhythmias, and pain. The purpose of the present review is to summarize existing knowledge of the pathophysiology, biophysics, and pharmacology of gating pore currents and to serve as a guide for future studies aimed at improving our understanding of gating pores and their pathophysiological roles.

Highlights

  • In the late 1940s, Hodgkin and Huxley were the first to highlight the importance of ionic movements in cell excitability

  • Iω/Iα : Normalization of the gating pore current to the maximum current of the alpha pore. ∗ For hHv1, the neutral residue in the R4 position appears to be involved in the creation of a conduction pathway through the Voltage sensor domains (VSDs)

  • Given the diversity of the gating pores investigated and the methods used to carry out the investigations, no consensus seems to have emerged concerning the conductance of gating pores

Read more

Summary

Introduction

In the late 1940s, Hodgkin and Huxley were the first to highlight the importance of ionic movements in cell excitability. They showed that the process was mediated by dedicated structures known as ion channels (Hodgkin and Huxley, 1952). At least 140 similar structures have been identified and assigned to the voltage gated ion channel (VGIC) superfamily (Yu and Catterall, 2004). Most of these VGICs (113 of 140) feature a voltage sensor domain (VSD) and belong to the VSD-featuring protein superfamily (Figure 1). Functional similarities, and structural homology, this superfamily can be divided into five main types: proteins lacking a PD, voltage gated sodium and calcium channels (Nav, Cav), voltage gated potassium channels (Kv), cyclic nucleotide gated channels (CNG), and transient receptors potential channels (TRPs)

Objectives
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call