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High-voltage activated Ca2+ (CaV) channels play a key role in the regulation of numerous physiological events by causing transient changes in the intracellular Ca2+ concentration. These channels consist of a pore-forming CaVα1 protein and three auxiliary subunits (CaVβ, CaVα2δ and CaVγ). CaVα2δ is an important component of CaV channels in many tissues and of great interest as a drug target. It is well known that anticonvulsant agent gabapentin (GBP) binds to CaVα2δ and reduces Ca2+ currents by modulating the expression and/or function of the CaVα1 subunit. Recently, we showed that an adamantane derivative of GABA, AdGABA, has also inhibitory effects on CaV channels. However, the importance of the interaction of AdGABA with the CaVα2δ subunit has not been conclusively demonstrated and the mechanism of action of the drug has yet to be elucidated. Here, we describe studies on the mechanism of action of AdGABA. Using a combined approach of patch-clamp recordings and molecular biology we show that AdGABA inhibits Ca2+ currents acting on CaVα2δ only when applied chronically, both in a heterologous expression system and in dorsal root-ganglion neurons. AdGABA seems to require uptake and be acting intracellularly given that its effects are prevented by an inhibitor of the l-amino acid transport system. Interestingly, a mutation in the CaVα2δ that abolishes GBP binding did not affect AdGABA actions, revealing that its mechanism of action is similar but not identical to that of GBP. These results indicate that AdGABA is an important CaVα2δ ligand that regulates CaV channels.