The alpha2delta ligand gabapentin inhibits the Rab11-dependent recycling of the calcium channel subunit alpha2delta-2.

ABSTRACT: The ?2? subunits of voltage-gated calcium channels are important modulatory subunits that enhance calcium currents and may also have other roles in synaptogenesis. The antiepileptic and antiallodynic drug gabapentin (GBP) binds to the ?2?-1 and ?2?-2 isoforms of this protein, and its binding may disrupt the binding of an endogenous ligand, required for their correct function. We have shown previously that GBP produces a chronic inhibitory effect on calcium currents by causing a reduction in the total number of ?2? and ?1 subunits at the cell surface. This action of GBP is likely to be attributable to a disruption of the trafficking of ?2? subunits, either to or from the plasma membrane. We studied the effect of GBP on the internalization of, and insertion into the plasma membrane of ?2?-2 using an ?-bungarotoxin binding site-tagged ?2?-2 subunit, and a fluorescent derivative of ?-bungarotoxin. We found that GBP specifically disrupts the insertion of ?2?-2 from post-Golgi compartments to the plasma membrane, and this effect was prevented by a mutation of ?2?-2 that abolishes its binding to GBP. The coexpression of the GDP-bound Rab11 S25N mutant prevented the GBP-induced decrease in ?2?-2 cell surface levels, both in cell lines and in primary neurons, and the GBP-induced reduction in calcium channel currents. In contrast, the internalization of ?2?-2 was unaffected by GBP. We conclude that GBP acts by preventing the recycling of ?2?-2 from Rab11-positive recycling endosomes to the plasma membrane.

SUBMITTER: Tran-Van-Minh A 

PROVIDER: S-EPMC6633565 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature