Resveratrol (REV) is a naturally occurring phytoalexin that inhibits neuronal K+ channels; however, the molecular mechanisms behind the effects of REV and the relevant α-subunit are not well defined. Using a patch clamp technique, cultured cerebellar granule cell and HEK-293 cells transfected with the Kv2.1 and Kv2.2 α-subunits, we investigated the effect of REV on Kv2.1 and Kv2.2 α-subunits. Our data have demonstrated that REV significantly suppressed Kv2.2 but not Kv2.1 currents with a fast, reversible and mildly concentration-dependent manner, and shifted the activation or inactivation curve of Kv2.2 channels. Activating or inhibiting cAMP/PKA pathway did not abolish the inhibition of Kv2.2 current by REV. In contrast, activation of PKC with PMA mimicked the inhibitory effect of REV on Kv2.2 with modifying the activation or inactivation properties of Kv2.2 channels and eliminated any further inhibition by REV. PKC and PKC- inhibitor completely eliminated the REV-induced inhibition of Kv2.2. Moreover, the effect of REV on Kv2.2 was reduced by pre-incubation with antagonists of GPR30 receptor and shRNA for GPR30 receptor. Western blotting results indicated that the levels of PKC-α and PKC-β were significantly increased in response to REV application. Our data reveal, for the first time, that REV inhibited Kv2.2 currents through PKC-dependent pathways and a nongenomic action of the oestrogen receptor GPR30.