Acid-sensing ion channels in ischemic stroke: amplifying and constraining neuronal injury in a phase-specific framework

Summary 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.