Mast cell degranulating peptide (MCD) induces long-term potentiation (LTP) in the CA1 region of the hippocampus. MCD has been shown to bind to a voltage-dependent A-type potassium channel with high-affinity (less than 1 nM). However, the concentration necessary to induce LTP is more than 500 nM, suggesting that some other functions of MCD are also fundamental to LTP induction. The concentration of MCD required for LTP induction was greatly reduced by preactivating G proteins. This fact suggests that G protein activation by MCD also plays an important role in LTP induction. MCD-binding proteins were purified from rat brain. G proteins were found to exist in a non-denatured state in this affinity-purified fraction. When reconstituted into a planar lipid bilayer membrane, a potassium-selective and voltage-dependent current could be observed. This channel was blocked by MCD at a high concentration equal to the effective concentration for G protein activation. Addition of GTP-gamma-S significantly blocked the reconstituted current. Thus, we identified a pathway for LTP induction by MCD in which high concentrations of MCD activate G protein which in turns leads to blocking of a potassium channel.