# Molecular determinants of ASIC1 modulation by divalent cations

## TL;DR

The study explores how divalent cations and small molecules modulate ASIC1a channels, revealing that cation binding in an acidic pocket is crucial for channel gating.

## Contribution

The study identifies the acidic pocket as a key site for divalent cation modulation of ASIC1a channel gating.

## Key findings

- Divalent cations bind to an acidic pocket site to modulate ASIC1a channel gating.
- Small molecules mimic divalent cation effects by binding to the same acidic pocket site.
- Mutations in ASIC1a affect channel gating and modulation by divalent cations.

## Abstract

Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. ASIC gating is modulated by divalent cations as well as small molecules; however, the molecular determinants of gating modulation by divalent cations are not well understood. Previously, we identified two small molecules that bind to ASIC1a at a novel site in the acidic pocket and modulate ASIC1 gating in a manner broadly resembling divalent cations, raising the possibility that these small molecules may help to illuminate the molecular determinants of gating modulation by divalent cations. Here, we examined how these two groups of modulators might interact as well as mutational effects on ASIC1a gating and its modulation by divalent cations. Our results indicate that binding of divalent cations to an acidic pocket site plays a key role in gating modulation of the channel.