Protein phosphorylation is important in synaptic transmission and plasticity. At the neuromuscular junction, phosphorylation of acetylcholine (ACh) receptor-channels increases the rate of agonist-induced channel desensitization. In contrast, potentiation of ACh channel activity through protein phosphorylation has not been described. We report here that calcitonin gene-related peptide (CGRP), a neuropeptide present at presynaptic motor nerve terminals, enhances the postsynaptic response at developing neuromuscular junctions by increasing the burst duration of embryonic ACh channels. The effect of CGRP on these ACh channels is mimicked by dibutyryl-cyclic AMP and by cAMP-dependent protein kinase (PKA) and prevented by a specific peptide inhibitor of PKA. Moreover, postsynaptic inhibition of PKA reduced the amplitude and decay time of spontaneous synaptic currents, suggesting that endogenous CGRP may act as a potentiating factor during the early phase of synaptogenesis.