%0 Journal Article %A Patrice M. Mich %A William A. Horne %T Alternative Splicing of the Ca2+ Channel β4 Subunit Confers Specificity for Gabapentin Inhibition of Cav2.1 Trafficking %D 2008 %R 10.1124/mol.108.045153 %J Molecular Pharmacology %P 904-912 %V 74 %N 3 %X Gabapentin is well established as an effective treatment for neuropathic pain; however, little is known about its mechanism of action. It binds with high affinity to Ca2+ channel α2δ subunits that are expressed in dorsal root ganglia. Mutation of a single α2δ amino acid, R217A, eliminates both gabapentin binding and analgesic efficacy. Gabapentin does not seem to have direct Ca2+ channel blocking properties but does affect overall levels of Ca2+ channel surface expression in some circumstances. In this report, we examined gabapentin effects on trafficking and voltage-dependent gating properties of recombinant Cav2.1 Ca2+ channel complexes transiently expressed in Xenopus laevis oocytes. We also determined electrophysiologically whether gabapentin causes displacement of β subunits from Cav2.1 complexes. Our principal findings are as follows: 1) gabapentin inhibits trafficking of recombinant Cav2.1 Ca2+ channels in X. laevis oocytes; 2) gabapentin inhibition occurs in the presence of the Ca2+ channel β4a subunit but not in the presence of β4b; 3) gabapentin does not affect Cav2.1 voltage-dependent gating parameters; 4) inhibition of Cav2.1trafficking is highly dependent on β-subunit concentration; and 5) gabapentin inhibition of Cav2.1 trafficking can be reversed by the α2δ R217A mutation. Overall, our results suggest that gabapentin reduces the number of β4a-bound Cav2.1 complexes that are successfully trafficked to the plasma membrane. This mechanism may help to explain why gabapentin is both effective and selective in the treatment of neuropathic pain states that involve up-regulation of α2δ subunits. %U https://molpharm.aspetjournals.org/content/molpharm/74/3/904.full.pdf