This project belongs to the field of neurobiology. Membrane ion channels are the basis of nerve cell excitability, and analyzing their biological functions has always been one of the core issues in neurobiology. Previous research on classical voltage or ligand-gated ion channels has greatly deepened people's understanding of the molecular basis of brain function. However, research on new membrane ion channels such as acid-sensing ion channels (ASICs) is seriously lagging behind. Facing this international scientific frontier, the project team has carried out systematic and original research on the biological functions, working principles and pathological significance of the two most representative subtypes of ASICs, ASIC1a and ASIC3, and achieved a series of new results: 1. The specific laws of the brain regions, cell types and cell organelles of ASICs distributed in the nervous system were revealed, and several unknown biological functions were discovered: ASIC1a is enriched in brain areas such as the dorsal horn of the spinal cord, insular cortex, cingulate cortex, hippocampus, striatum and amygdala; at the cellular level, all subtypes of ASICs are mainly distributed in neurons rather than glial cells; for the first time, functional ASIC1a (named mtASIC1a) was observed to be expressed on the inner membrane of mitochondria. On this basis, we focused on studying the common rules of ASIC1a regulating synaptic transmission and plasticity in multiple brain regions. This series of studies has laid an important foundation for revealing the biological functions of ASICs and the pathophysiological significance of their abnormalities.  2. In terms of the working principle of ASIC, focus on the two core scientific issues of proton gating and acid signal transduction. The project team broke through traditional understanding and created the ASIC3 non-proton gating hypothesis; for the first time, it revealed the metabolic allosteric signal transduction mechanism of ASIC1a and expanded new understanding of ASIC signal transduction. At the same time, it was the first to identify the aprotic ligand receptor domain of ASIC3, and selected multiple new aprotic ligands, which were developed into commercial tool drugs to clarify the pathophysiological significance of ASIC3 and promote the formation of related research. New direction.  3. Facing the need for the prevention and treatment of major brain diseases, we broke through the bottleneck of the theory of excitotoxicity that has long been dominant in the field of stroke, and creatively proposed and verified that under stroke conditions, ASIC1a mediates excitotoxicity caused by glutamate and acidosis caused by tissue acidification. The synergy between acidosis enriched and developed the hypothesis of acidosis nerve damage; using chronic pain models, we also systematically studied the relationship between dysfunction of ASIC1a in the spinal cord pain conduction center and cerebral cortex and chronic pain. In addition, the cellular biological mechanism that controls the number of ASIC1a channels on the plasma membrane and its abnormal mechanism under stroke and chronic pain conditions were analyzed, providing a theoretical basis for future translational medicine research based on the biological functions and working principles of ASICs.  The project team published more than 30 original papers related to ASICs, of which 8 representative papers were reviewed or cited 553 times by Nature, Science, Cell, Neuron, Nat Rev Neurosci, Physiol Rev, Pharmacol Rev, etc., and the maximum number of citations for a single article was 172 times. Invited to write special reviews for Prog Neurobiol and Sci China ndash; Life Sci and Journal of Physiology. More than 40 graduate students have been trained, of which 13 graduate students and/or young teachers have grown into professors/researchers in well-known universities and scientific research institutions at home and abroad, including co-applicants Professor Gao Jun (National Excellent Youth) and Professor Yu Ye (National Excellent Youth), Young Yangtze River). Co-applicant Researcher Jiang Hualiang was elected as an academician of China Academy of Sciences in 2017.