Proton-Sensitive Receptors/Channels: Therapeutic Target for Ischemic Stroke, Focusing on Their Roles and Mechanisms

Ischemic stroke is a common cerebrovascular disease. However, its pathophysiological mechanisms and therapeutic targets remain unclear. In physiological states, the brain maintains an acid-base balance through various mechanisms that are crucial for normal brain function. However, during cerebral ischemia, the disruption of this balance leads to acidosis of the ischemic brain tissue, primarily due to the interruption of energy supply and alterations in ion homeostasis. Studies have indicated that proton-sensitive receptors/channels, such as acid-sensing ion channels, protonsensitive G-protein-coupled receptors, and proton-activated chloride channels, exhibit distinct mechanisms in response to decreased pH. These targets are intricately linked to the pathophysiological processes, such as neuroprotection, neurorestoration, and neuroinflammation, underlying ischemic stroke. Recent studies have uncovered novel patterns of recognition, activation, subcellular distribution, and emerging functions of these proton-sensing receptors/channels, offering deeper insights into their roles and mechanisms in ischemic brain injury. This review summarizes the current insights regarding different contributions of these proton-sensing receptors/channels following ischemic stroke, and highlights the significance of targeting them for advancing novel therapeutic strategies for stroke intervention.