The α2δ auxiliary subunits of voltage-gated calcium channels enhance calcium currents and affect their properties, but their mechanism of action is not well understood. We have recently shown that α2δ subunits can form glycosyl phophatidyl inositol (GPI)-achored proteins (Davies et al., 2010), and this is essential for their function, and explains their localization in lipid raft fractions (Davies et al, 2006). The anti-epileptic and anti-nociceptive drugs gabapentin (GBP) and pregabalin (PGB) are known to bind to α2δ-1 and α2δ-2, and the α2δ-1 target is essential for the antihyperalgesic action of this drug (Field et al., 2006). We have found that acute application of GBP does not affect calcium currents in several different systems. However, chronic application of GBP to cultured cells reduces both calcium currents and cell-surface expression of heterologously expressed α2δ and α1 subunits (Hendrich et al., 2008), and PGB also affects α2δ trafficking in vivo (Bauer et al., 2009). This process involves an inhibition of trafficking through the recycling endosomes (Tran-Van-Minh and Dolphin, 2010). Our evidence indicates that gabapentinoid drugs act chronically to impair the trafficking function of α2δ subunits.