The binding mode of picrotoxinin in GABA_A-ρ receptors: Insight into the subunit's selectivity in the transmembrane domain

The channel blocker picrotoxinin has been studied with GABA_A-ρ1 and GABA_A-ρ2 homology models based on the GluCl crystal structure. Picrotoxinin is tenfold more potent for GABA_A-ρ2 than for GABA_A-ρ1 homomeric channels. This intra-subunit selectivity arises from the unconserved residues at the 2’ sites, which are the essential molecular basis for both the binding and potency of picrotoxinin. The serine residues at the 2’ positions of the ρ2 channel are predicted to form multiple hydrogen bonds and hydrophobic interactions with picrotoxinin, whereas the proline residues in the 2’ positions of ρ1 channels are predicted to form only hydrophobic contacts with picrotoxinin. However, although the studied ρ1 P2’G, A, and V models form no hydrogen bonds with picrotoxinin, they may participate in several hydrophobic interactions, and the ligand may have distinctive binding modes with GABA_A-ρ mutant channels. Picrotoxinin has a lower Emodel value with ρ2 than ρ1 homomeric models (−47 Kcal/mol and −36 Kcal/mol, respectively), suggesting that picrotoxin blocks the pores of the ρ2 channels more effectively.