Mammalian neuronal cells abundantly express a de‐ubiquitinating isozyme, ubiquitin carboxy‐terminal hydrolase L1 (UCH L1). Loss of UCH L1 function causes dying‐back type of axonal degeneration. However, the function of UCH L1 in neuronal cells remains elusive. Here we show that overexpression of UCH L1 potentiated ATP‐induced currents due to the activation of P2X receptors that are widely distributed in the brain and involved in various biological activities including neurosecretion. ATP‐induced inward currents were measured in mock‐, wild‐type or mutant (C90S)‐UCH L1‐transfected PC12 cells under the conventional whole‐cell patch clamp configuration. The amplitude of ATP‐induced currents was significantly greater in both wild‐type and C90S UCH L1‐transfected cells, suggesting that hydrolase activity was not involved but increased level of mono‐ubiquitin might play an important role. The increased currents were dependent on cAMP‐dependent protein kinase (PKA) and Ca²⁺ and calmodulin‐dependent protein kinase (CaMKII) but not protein kinase C. In addition, ATP‐induced currents were likely to be modified via dopamine and cyclic AMP‐regulated phosphoprotein (DARPP‐32) that is regulated by PKA and phosphatases. Our finding shows the first evidence that there is a relationship between UCH L1 and neurotransmitter receptor, suggesting that UCH L1 may play an important role in synaptic activity.