ASIC1a ligand-gated ion channel assay
Application report
Application report title
ASIC1a ligand-gated ion channel assay
Summary
Rapidly activating and desensitising ligand-gated ion channel receptors can provide a technical challenge on automated patch clamp electrophysiology platforms. This can affect their biophysics, pharmacology and assay reliability. We present data on an optimised and validated acid-activated receptor assay on the QPatch that is stable enough for drug discovery screening.
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Extract
Introduction
Acid-Sensing Ion Channels (ASICs) are voltage-insensitive Na+ channels that are classified in a subfamily of the degenerin/epithelial Na+ channel (ENaC) superfamily1. Four ASIC genes (ASIC1, ASIC2, ASIC3, and ASIC4) have been identified in mammals, which encode a total of six ASIC subunit isoforms, including ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC42. Each subunit contains two transmembrane domains and a pore-forming region (Figure 1A), and functional channels are composed of three subunits (Figure 1B). The subunits are capable of forming either homo- or heterotrimers, which exhibit different sensitivities to activation by extracellular protons2. ASIC subunits possess large extracellular regions that contain the proton binding site, which upon occupation can allosterically activate the channel and open the cation-conducting pore.
ASIC1a is expressed in various regions of the brain, including the hippocampus, cerebral cortex, cerebellum, and amygdala3 Elevated neural activity can lower the pH of the extracellular environment into a range capable of activating ASIC1a channels, which leads to an influx of Na+ and depolarisation of the cell membrane. Additionally, homomeric ASIC1a channels are permeable to Ca2+ so excessive activation can contribute to neurotoxicity4,5.
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