Neuropharmacology 2001 Dec 01;417:854-61. doi: 10.1016/s0028-3908(01)00137-x.

Inhibition of nicotinic acetylcholine receptors by bicuculline.

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A study was made on the effects of bicuculline, the classical gamma-aminobutyric acid-A receptor antagonist, on heteromeric mouse muscle alphabetagammadelta, heteromeric neuronal rat alpha2beta4 and alpha4beta2 and homomeric human alpha7 nicotinic acetylcholine receptors (nAChRs), expressed in Xenopus oocytes. Bicuculline reduced the ACh-induced currents in a rapid and reversible way, with IC50 values of 34+/-1.5 microM for mouse muscle alphabetagammadelta and 12.4+/-0.7 and 18+/-1 microM for rat neuronal alpha2beta4 and alpha4beta2 nAChRs, respectively. Therefore, the three types of heteromeric receptors are inhibited by bicuculline but the neuronal alpha2beta4 and alpha4beta2 receptors were more sensitive than the muscle alphabetagammadelta receptor. The Hill coefficients for ACh-current inhibition were close to one for all types of receptors, suggesting a single site of action for bicuculline inhibition of nAChRs. Bicuculline shifted the ACh-dose-current response curve to the right and the maximal current was reduced, a reduction that for the heteromeric receptors was not overcome by high concentrations of ACh. The effect of bicuculline was examined at different membrane potentials, and the ACh-current-membrane potential relationships obtained indicate that the inhibition by bicuculline is voltage-dependent for muscle alphabetagammadelta and neuronal alpha2beta4 and alpha4beta2 nAChRs. All these results are consistent with the notion that bicuculline blocks the heteromeric muscle and neuronal nAChRs in a non-competitive way. Studies were also made on the wild type (wt alpha7) and mutant leu-to-threo (L248T) homomeric human neuronal alpha7-nAChRs. In sharp contrast to the heteromeric ACh receptors examined, bicuculline blocked in a competitive way the homomeric wt alpha7-nAChRs, as evidenced by a parallel shift of the bicuculline dose-ACh-current inhibition on raising the ACh concentration. Moreover, similar to the effects of serotonin on wt and mutant alpha7 ACh receptors, the mutation converted bicuculline from an antagonist into a competitive agonist. All this suggests that bicuculline may serve as a lead molecule to design new anticholinergic substances.

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