Understanding the Pathological Mechanism of Acid Sensing Ion Channels as a Manner of Mitigating Acid-Induced Neurodegeneration

Abstract

Acidosis is a contributor to neuronal injury in various neurological disorders including cerebral ischemia, multiple sclerosis, and traumatic injury. Acid induced toxicity in the central nervous system is dependent on Acid Sensing Ion Channels (ASICs) which sense extracellular pH reductions and induce neuronal depolarization. Although ASICs are necessary for normal synaptic transmission, ASIC activation can also have acidotoxic effects that lead to neuronal degeneration. Yet, strategies to inhibit ASIC-mediated cell death are few. In our studies of neuropeptide modulation of ASICs, we discover the Delta Opioid Receptor (DOR) has neuroprotective actions via signaling cascades and seems to inhibit ASIC-mediated cell death through indirect or downstream mechanisms. This observation presents a potential therapeutic target to limit neuronal injury, but the neuroprotective mechanism is not understood. In particular, new data indicate protein-protein interactions are critical for ASIC-mediated toxicity. Receptor Interacting Protein Kinase 1 (RIP1) signaling has been shown to mediate cell death and pharmacological studies have suggested that ASIC-mediated RIP1 activation is a key step in ischemic brain injury, yet we were not able to consistently reproduce these results. In order to test whether DOR-induced neurodegeneration, we utilized both coimmunoprecipitation methods and proximity labelling to study the impacts of ASIC protein-protein interactions. By studying the protein-protein interactions that are occurring at the pathological level in ASICs, we will be able to further understand the mechanism of ASIC-dependent acidosis in order to further pursue therapeutic targets to protect against neuronal injury.