Acid-sensing ion channels in ischemic stroke: amplifying and constraining neuronal injury in a phase-specific framework.
5 affiliations
- 1Program in Neurosciences and Mental Health, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
- 2Program in Developmental, Stem Cell, and Cancer Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
- 3Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
- 4Department of Anatomy and Physiology, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- 5Department of Anatomy and Physiology, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
Abstract
For decades, ischemic neuronal death was understood largely as a story about glutamate. Acid-sensing ion channels (ASICs) have revised that account. When cerebral blood flow stops, the penumbra can develop prolonged extracellular acidosis, and experimental studies implicate ASIC1a in mediating sufficient Ca²⁺ entry to injure neurons even when glutamate receptors are blocked, a contribution shaped by channel expression, subunit composition, and the intracellular signaling context. However, sustained acidosis does not necessarily imply sustained channel opening, given ASIC1a desensitization. Besides acidosis, glutamate, polyamines, a paradoxical intracellular alkalization, and oxidative stress can enhance ASIC1a activity or expression, and the channel also signals through a non-conducting route, recruiting RIPK1 to trigger necroptosis independently of ion flux. The relative contributions of these conducting and non-conducting mechanisms in vivo remain incompletely defined. Endogenous mechanisms may constrain injury by internalizing the channel, altering subunit expression, including conditioning-associated ASIC2a upregulation, and degrading ASIC1a through estrogen signaling. We argue that these responses are better understood as constraints on injury than as a genuine survival program, a distinction with mechanistic and therapeutic consequences. Critically, the contribution of these mechanisms may vary over time. The same channel acts as a target of homeostatic regulation before stroke, a driver of death during ischemia, a potential target at reperfusion when acidosis persists but restored flow finally permits drug delivery, and an impediment to repair for weeks afterward. The question in ASIC-targeted neuroprotection is not only whether to inhibit the channel, but also when and for how long.
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BibTeX
@article{weng2026acidsensing,
title = {{Acid-sensing ion channels in ischemic stroke: amplifying and constraining neuronal injury in a phase-specific framework.}},
author = {Octavia Yifang Weng and Jian-Fei Lu and Xin Qi and Xi Chen and Lu-Yang Wang and Tian-Le Xu},
journal = {Pflugers Archiv : European journal of physiology},
year = {2026},
month = oct,
doi = {10.1007/s00424-026-03217-5},
url = {https://europepmc.org/article/MED/42850478},
note = {CC BY},
}
RIS
TY - JOUR
TI - Acid-sensing ion channels in ischemic stroke: amplifying and constraining neuronal injury in a phase-specific framework.
AU - Octavia Yifang Weng
AU - Jian-Fei Lu
AU - Xin Qi
AU - Xi Chen
AU - Lu-Yang Wang
AU - Tian-Le Xu
PY - 2026
DA - 2026/10/09
JO - Pflugers Archiv : European journal of physiology
DO - 10.1007/s00424-026-03217-5
UR - https://europepmc.org/article/MED/42850478
AB - For decades, ischemic neuronal death was understood largely as a story about glutamate. Acid-sensing ion channels (ASICs) have revised that account. When cerebral blood flow stops, the penumbra can develop prolonged extracellular acidosis, and experimental studies implicate ASIC1a in mediating sufficient Ca²⁺ entry to injure neurons even when glutamate receptors are blocked, a contribution shaped by channel expression, subunit composition, and the intracellular signaling context. However, sustained acidosis does not necessarily imply sustained channel opening, given ASIC1a desensitization. Besides acidosis, glutamate, polyamines, a paradoxical intracellular alkalization, and oxidative stress can enhance ASIC1a activity or expression, and the channel also signals through a non-conducting route, recruiting RIPK1 to trigger necroptosis independently of ion flux. The relative contributions of these conducting and non-conducting mechanisms in vivo remain incompletely defined. Endogenous mechanisms may constrain injury by internalizing the channel, altering subunit expression, including conditioning-associated ASIC2a upregulation, and degrading ASIC1a through estrogen signaling. We argue that these responses are better understood as constraints on injury than as a genuine survival program, a distinction with mechanistic and therapeutic consequences. Critically, the contribution of these mechanisms may vary over time. The same channel acts as a target of homeostatic regulation before stroke, a driver of death during ischemia, a potential target at reperfusion when acidosis persists but restored flow finally permits drug delivery, and an impediment to repair for weeks afterward. The question in ASIC-targeted neuroprotection is not only whether to inhibit the channel, but also when and for how long.
SN - 0031-6768
SN - 1432-2013
ER -