# Zinc Permeation Through Acid-Sensing Ion Channels

## TL;DR

Zinc can pass through ASIC2a channels, and this may worsen brain injury in acidic conditions like those seen during severe ischemia.

## Contribution

Discovery that ASIC2a channels allow zinc influx and may contribute to neuronal injury under acidic conditions.

## Key findings

- ASIC2a channels are permeable to zinc under acidic conditions.
- Zinc influx through ASIC2a channels exacerbates acid-induced neurotoxicity.
- Zinc-induced currents are observed in cells expressing ASIC2a but not ASIC1a.

## Abstract

What are the main findings?
Acid-sensing ion channel 2a (ASIC2a)-containing channels are permeable to zinc.Zinc enhances neuronal injury under severe acidic conditions.

Acid-sensing ion channel 2a (ASIC2a)-containing channels are permeable to zinc.

Zinc enhances neuronal injury under severe acidic conditions.

What is the implication of the main findings?
ASIC2a may play a role in zinc toxicity under low pH conditions such as in severe ischemia.

ASIC2a may play a role in zinc toxicity under low pH conditions such as in severe ischemia.

Acid-sensing ion channels (ASICs), activated under acidic conditions, play a critical role in ischemic brain injury, but the detailed mechanisms and signaling pathways remain unclear. Our previous studies have shown that activation of ASIC1a channels contributes to acidosis-induced neuronal injury, partially mediated by increased calcium influx. In this study, we provide evidence that activation of ASIC2a-containing channels induces zinc influx. In cultured mouse cortical neurons, ASIC currents that were insensitive to PcTx1 inhibition were potentiated by extracellular zinc. In Chinese Hamster Ovary cells transfected with different ASIC subunits, large inward currents were recorded upon a pH drop from 7.4 to 5.0 in cells expressing homomeric ASIC1a, ASIC2a, or heteromeric ASIC1a/2a channels when normal Na+-rich extracellular fluid (ECF) was used. However, when ECF was modified to one containing zinc as the primary cation, the same pH drop induced an inward current only in cells expressing homomeric ASIC2a or heteromeric ASIC1a/2a, but not homomeric ASIC1a. Fluorescence imaging revealed rapid zinc influx in cells expressing ASIC2a but not ASIC1a when zinc was applied with the acidic ECF. Additionally, at pH values where ASIC2a-containing channels were activated, acid-mediated neurotoxicity was exacerbated by zinc. Thus, ASIC2a-containing channels may represent a novel pathway for zinc entry and activation of these channels might contribute to zinc-mediated neurotoxicity.