Structural requirement of the calcium-channel subunit α2δ for gabapentin binding

摘要: Gabapentin [Neurontin, 1-(aminomethyl)cyclohexaneacetic acid] is a novel anticonvulsant drug with high binding affinity for the Ca 2+ -channel subunit α 2 δ. In this study, gabapentin-binding properties of wild-type and mutated porcine brain δ proteins were investigated. Removal disulphide bonds between subunits did not result in significant loss gabapentin binding, suggesting that linkage two required binding. Singly expressed protein remained membrane associated. However, alone was unable to bind gabapentin, unless cells concurrently transfected expression vector δ, both are Using internal deletion mutagenesis, we mapped regions [amino acid residues 339-365 (δF) 875-905 (δJ)] within Further, three other individual 206-222 (δD), 516-537 (δH) 583-603 (δI)] disrupted structural importance these regions. alanine replace four six amino each abolished These results demonstrate region D, N-terminal end first putative transmembrane domain , H I, splicing acceptor sites (Gln 511 Ser 601 ), may play important roles maintaining integrity Further single replacement mutagenesis identified Arg 217 as critical