The β ‐lactam antibiotics, penicillin‐G and cefoselis have different mechanisms and sites of action at GABA A receptors

The action of the β‐lactam antibiotics, penicillin‐G (PCG) and cefoselis (CFSL) on GABA A receptors (GABA A ‐R) was investigated using the two‐electrode voltage clamp technique and Xenopus oocyte expressed murine GABA A ‐R. Murine GABA A ‐Rs were expressed in Xenopus oocytes by injecting cRNA that encoded for each subunit (α1, β2, and γ2) and the effects of PCG and CFSL on the α1β2γ2s subunit receptors were examined using two‐electrode voltage clamp. Using the α1β2γ2s GABA A ‐R, PCG and CFSL inhibited GABA‐induced currents in a concentration‐dependent manner, with IC 50 s of 557.1±125.4 and 185.0±26.6 μ M , respectively. The inhibitory action of PCG on GABA‐induced currents was non‐competitive whereas that of CFSL was competitive. Mutation of tyrosine to phenylalanine at position 256 in the β2 subunit (β2 Y256F ), which is reported to abolish the inhibitory effect of picrotoxin, drastically reduced the potency of PCG (IC 50 =28.4±1.42 m M ) for the α1β2 Y256F γ2s receptor without changing the IC 50 of CFSL (189±26.6 μ M ). These electrophysiological data indicate that PCG and CFSL inhibit GABA A ‐R in a different manner, with PCG acting non‐competitively and CFSL competitively. The mutational study indicates that PCG might act on an identical or nearby site to that of picrotoxin in the channel pore of the GABA A ‐R.British Journal of Pharmacology (2001) 135 , 427–432; doi: 10.1038/sj.bjp.0704496