Zinc Permeation Through Acid-Sensing Ion Channels

Area of Science:

• Neuroscience
• Ion Channel Physiology
• Cellular Signaling

Background:

• Acid-sensing ion channels (ASICs) are crucial in ischemic brain injury.
• ASIC1a activation increases calcium influx, contributing to neuronal damage.
• Mechanisms of ASIC-mediated neurotoxicity, especially involving other ions, are not fully understood.

Purpose of the Study:

• To investigate the role of ASIC2a-containing channels in ion flux and neurotoxicity.
• To determine if ASIC2a channels mediate zinc influx.
• To explore the contribution of zinc to acid-mediated neurotoxicity.

Main Methods:

• Utilized cultured mouse cortical neurons and Chinese Hamster Ovary (CHO) cells expressing ASIC subunits.
• Measured ASIC currents using electrophysiology under varying pH and extracellular cation conditions (Na+, Zn2+).
• Employed fluorescence imaging to visualize zinc influx and assessed neurotoxicity in the presence of zinc and acidic conditions.

Main Results:

• ASIC currents insensitive to PcTx1 were potentiated by extracellular zinc.
• ASIC2a-containing channels (homomeric ASIC2a and heteromeric ASIC1a/2a) facilitated zinc influx upon acid stimulation, unlike homomeric ASIC1a.
• Zinc exacerbated acid-mediated neurotoxicity in cells expressing ASIC2a-containing channels.

Conclusions:

• ASIC2a-containing channels represent a novel pathway for zinc entry into neurons.
• Acid-induced activation of ASIC2a channels can lead to zinc influx.
• This zinc influx mediated by ASIC2a channels may contribute to neurotoxicity.