TRPC3‐Driven Calcium Microdomains Instruct Peripheral Nerve Regeneration With Protective Implications for Central Neurons

ABSTRACT A central challenge in neural repair is the “calcium paradox”: while Ca 2+ is essential for neuronal growth, global elevations often trigger toxicity rather than repair. Spontaneous near‐membrane Ca 2+ microdomains (smCa) have been identified in sensory neurons, yet their molecular origin and functional role in repair remain unclear. Here, by resolving Ca 2+ dynamics at sub‐cellular resolution, we show that TRPC3 drives smCa hotspots, which function as a localized signaling module that avoids global toxicity to instruct repair. Using peripheral sensory neurons as a primary model, we show that TRPC3‐smCa constitutes a basic instructive unit that appears both necessary and sufficient to initiate axon regeneration, a process that involves calmodulin‐dependent pathways. Following sciatic nerve injury, TRPC3‐smCa axis is essential for structural and functional recovery. Our data further suggest that this repair module also operates in central nervous system: in midbrain dopaminergic neurons, TRPC3‐smCa is associated with a neuroprotective state, correlating with enhanced neuronal survival and motor function in a Parkinson's disease model. This pro‐repair correlation is further observed in human ESC‐derived dopaminergic neurons. Collectively, our findings identify TRPC3‐driven Ca 2+ microdomains as a repair module, pointing to a spatial logic for neural repair with potential relevance for nerve injury and neurodegenerative disorders.