Of a variety of saturated free fatty acids examined here, those with less than 20 hydrocarbon potentiated responses through Torpedo ACh receptors expressed in Xenopus oocytes, and the maximal effect was obtained with stearic acid (C18:0) at 10 μM (168+/-25% of basal levels 10 min after 10-min treatment). Stearic aid (10 μM) also potentiated α7 nicotinic ACh receptor responses, being evident 110 min after 10-min treatment (219+/-18% of basal levels), and the potentiation was inhibited by GF109203X, a selective inhibitor of protein kinase C (PKC). In the PKC assay using a reversed-phase HPLC, stearic acid (10 μM) enhanced PKC-ε activity approximately twice as much as the activity in the absence of stearic acid. Stearic acid (10 μM) induced a long-lasting facilitation of neurotransmission in the dentate gyrus of rat hippocampal slices, and the facilitation was inhibited by GF109203X or α-bungarotoxin, an inhibitor of α7 receptors. The results presented here suggest that stearic acid facilitates hippocampal neurotransmission by enhancing α7 receptor responses via a PKC pathway.