Key result
Ion channel gating pores, caused by mutations in voltage sensor domains, create alternative permeation pathways linked to channelopathies such as periodic paralysis and represent novel therapeutic targets.
This review summarizes the pathophysiology and pharmacology of ion channel gating pores, highlighting their role in excitability disorders like cardiac arrhythmias and epilepsy, and their potential as novel therapeutic targets.
Gating pore currents may identify novel targets in arrhythmias and epilepsy; leaves open selective drug development and clinical validation.
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.
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Moreau et al. (2014) conducted a review in Ion channelopathies (e.g., periodic paralysis). Ion channel gating pores was evaluated. Ion channel gating pores, caused by mutations in voltage sensor domains, create alternative permeation pathways linked to channelopathies such as periodic paralysis and represent novel therapeutic targets.
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