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Replacement of asparagine with arginine at the extracellular end of the second transmembrane (M2) region of insect GABA receptors increases sensitivity to penicillin G.

Hosie, AM; Buckingham, SD; Hamon, A; Sattelle, DB; (2006) Replacement of asparagine with arginine at the extracellular end of the second transmembrane (M2) region of insect GABA receptors increases sensitivity to penicillin G. Invert Neurosci , 6 (2) pp. 75-79. 10.1007/s10158-006-0020-4.

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Abstract

The actions of penicillin-G (PCG) on wild-type and mutant Drosophila GABA receptor (RDL) subunits expressed in Xenopus oocytes were studied under two-electrode voltage-clamp. PCG was found to be a non-competitive antagonist of homomeric Drosophila RDL receptors with an IC(50) of 20.41 +/- 1.66 mM at EC(50) GABA. Substitution of a single amino acid (N318R) at the extracellular end of the channel lining region of the RDL subunit increased the potency of GABA approximately four fold, and increased the IC(50) of PCG to 5.09 +/- 0.38 mM. Although the antagonism by PCG on wild-type RDL receptors was independent of membrane potential, PCG action on the N318R mutant showed pronounced voltage-dependency, being much more effective at positive membrane potentials. Thus, in RDL homomers, the replacement of N318 by R318, a residue present at the equivalent position in vertebrate GABA(A) receptors, confers a vertebrate-like PCG pharmacology to the N318R mutant receptor. The A301S mutation that confers resistance to dieldrin did not significantly affect the antagonism by PCG.

Type: Article
Title: Replacement of asparagine with arginine at the extracellular end of the second transmembrane (M2) region of insect GABA receptors increases sensitivity to penicillin G.
Location: Germany
DOI: 10.1007/s10158-006-0020-4
Keywords: Animals, Arginine, Asparagine, Dose-Response Relationship, Drug, Drosophila, GABA Antagonists, GABA Modulators, Inhibitory Concentration 50, Insect Proteins, Insecta, Membrane Potentials, Models, Molecular, Mutagenesis, Site-Directed, Mutation, Oocytes, Patch-Clamp Techniques, Penicillin G, Receptors, GABA, Xenopus
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/1482914
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