Acid-Sensing Ion Channels: Gatekeepers of Chronic Pain

ACS Chem Neurosci. 2026 Jun 4. doi: 10.1021/acschemneuro.6c00054. Online ahead of print.

ABSTRACT

Chronic pain typically develops in situations such as tissue injury, inflammation, and ischemia, where extracellular acidity increases in the altered microenvironment. Acid-sensing ion channels (ASICs) are proton-gated membrane proteins that enable sensory neurons to detect these pH changes and convert them into electrical signals. Emerging evidence suggests that specific ASIC subtypes, particularly ASIC1a and ASIC3, contribute to nociceptive signaling, peripheral sensitization, and neuroinflammatory responses. Recent structural studies have bettered our understanding of ASIC architecture and gating mechanisms, while functional studies have revealed their interactions with multiple intracellular signaling pathways involved in pain modulation. This review summarizes current understanding of ASIC structure, activation mechanisms, and their role in inflammation-associated pain pathways. We also discuss emerging pharmacological strategies aimed at altering ASIC activity. A clearer understanding of ASIC-mediated signaling may help identify new therapeutic approaches for the management of chronic pain and related neurological disorders.

PMID:42240966 | DOI:10.1021/acschemneuro.6c00054