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TRPV1 is a non-selective cationic channel that is activated by capsaicin, acidic pH and thermal stimuli. Sustained TRPV1 channel activation causes severe cytotoxicity that leads to cell death. In this study, we investigated the mechanisms of capsaicin-induced cytotoxicity in HEK293 cells stably expressing TRPV1 with a focus on protein synthesis regulation and cytoskeleton reorganization. Capsaicin inhibited protein synthesis in TRPV1-expressing HEK cells with an IC50 of 15.6 nM and depolymerized microtubules within 10 min after exposure. These effects were completely blocked by pretreatment of cells with the TRPV1 antagonist A-425619, both in the presence and absence of extracellular calcium. Protein synthesis inhibition induced by capsaicin was not a result of eIF2α hyperphosphorylation, but rather closely correlated with cytosolic calcium elevation caused by calcium flux through cell surface and intracellular TRPV1, and/or ER calcium depletion through intracellular TRPV1. Microtubule dependent cell process shrinkage may serve as a mechanism for rapid alteration of the neurotransmission network upon TRPV1 activation. Taken together, the present studies demonstrate that intracellular pool of TRPV1 plays an important role in regulating cell morphology and viability upon receptor activation.