Proton-gated channels of the acid-sensing ion channel (ASIC) family are candidates for mediating the fast ionotropic transduction of extracellular acidification in neurons. ASIC subunits can assemble in homomeric and heteromeric channels with specific biophysical and pharmacological properties. Using heterologous expression of ASIC subunits in Xenopus oocytes, we show here that the biphasic response of heteromeric rat and human ASIC2A+3 subtypes to low pH is selectively modulated by the neuropeptide FF (NPFF) and by the related peptide FMRFamide. We recorded both a dramatic potentiation (up to 275%) of the amplitude of acid-gated human ASIC2A+3 maximal currents and a change of desensitization kinetics in the presence of NPFF (EC(50)=2 microM) leading to a slowly inactivating phenotype. These modulatory effects were not observed with the corresponding homomeric human ASIC2A or ASIC3 receptor subtypes. Moreover, the sensitivity of ASIC2A+3 receptors to extracellular protons was increased in the presence of NPFF (DeltapH(50)=+0.5). Our data therefore suggest that the direct sensitization of heteromeric proton-gated channels by endogenous neuropeptides might play a role in the neuronal response to noxious acidosis in sensory and central pathways.