Neuropharmacology 2003 May 01;446:765-71. doi: 10.1016/s0028-3908(03)00054-6.

Properties of neuronal alpha7 mutant nicotinic acetylcholine receptors gated by bicuculline.

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We have shown previously that mutating to threonine the leucine residue in the M2 domain of the alpha7 nicotinic acetylcholine receptor (human L248T, L248T; chick L247T, L247T) converts bicuculline (BIC) from an antagonist into an agonist. In this work we studied the functional properties of the BIC-activated channels and report that, in Xenopus oocytes injected with L248T subunit cDNA, BIC activates single-channel currents that have similar conductances, but shorter mean burst duration, than the channels activated by ACh. In contrast, both the conductance and kinetics of the channels activated by either ACh or BIC are substantially the same in oocytes expressing L247T receptors. We have also shown previously that if Cys 189 and 190, which are thought to be at or near the transmitter binding site, are additionally mutated to Ser, the new mutant receptor (L247T-C189S-C190S) has a reduced affinity for ACh. We now find that the EC(50) in the BIC dose-current response relation, as well the characteristics of the channels activated by BIC, are similar in oocytes expressing either L247T or L247T-C189S-C190S receptors. On the other hand, ACh activation of L247T-C189S-C190S receptors gates channels whose mean open time and burst duration are much shorter than those of ACh-gated L247T-channels. Therefore, the gating kinetics of both L248T and L247R-C189S-C190S receptor-channels change when BIC is replaced by ACh; and we conclude that both ACh and BIC activate mutant alpha7 receptors with different patterns of activation.

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