The modulation of neurotransmitter receptor density is an important molecular mechanism underlying synaptic plasticity. Acid-sensing ion channel 1a (ASIC1a), a receptor for protons, plays an important role in synaptic transmission. In this study, we used high-resolution proteomic analysis to identify prenylcysteine oxidase 1 like (PCYOX1L) as a hitherto unknown interaction partner of ASIC1a. We found that PCYOX1L is a secreted protein that promotes ASIC1a assembly. PCYOX1L was indispensable for ASIC1a expression in the plasma membrane and synaptosomes, and the genetic deletion of PCYOX1L severely impaired hippocampal long-term potentiation. Endocytosed PCYOX1L promoted plasma membrane expression of ASIC1a, and PCYOX1L secreted from astrocytes induced ASIC1a activity in neurons. Our findings reveal that a secreted protein, PCYOX1L, is a checkpoint for the plasma membrane expression of a synaptic ion channel.