title: Context-dependent modulation of alphabetagamma and alphabetadelta GABA A receptors by penicillin: implications for phasic and tonic inhibition.
abstract: Penicillin, an open-channel blocker of GABA(A) receptors, was recently reported to inhibit phasic, but not tonic, currents in hippocampal neurons. To distinguish between isoform-specific and context-dependent modulation as possible explanations for this selectivity, the effects of penicillin were evaluated on recombinant GABA(A) receptors expressed in HEK293T cells. When co-applied with saturating GABA, penicillin decreased peak amplitude, induced rebound, and prolonged deactivation of currents evoked from both synaptic and extrasynaptic receptor isoforms. However, penicillin had isoform-specific effects on the extent of desensitization, reflecting its ability to differentially modulate peak (non-equilibrium) and residual (near-equilibrium) currents. This suggested that the context of activation could determine the apparent sensitivity of a given receptor isoform to penicillin. To test this hypothesis, we explored the ability of penicillin to modulate synaptic and extrasynaptic isoform currents that were activated under more physiologically relevant conditions. Interestingly, while currents evoked from synaptic isoforms under phasic conditions (transient activation by a saturating concentration of GABA) were substantially inhibited by penicillin, currents evoked from extrasynaptic isoforms under tonic conditions (prolonged application by a sub-saturating concentration of GABA) were minimally affected. We therefore concluded that the reported inability of penicillin to modulate tonic currents could not simply be attributed to insensitivity of extrasynaptic receptors, but rather, reflected an inability to modulate these receptors in their native context of activation.
authors.affiliation: Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Feng
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Botzolakis
authors.forename: Robert L
authors.initials: RL
authors.lastname: Macdonald
mesh_terms: D002461:Cell Line, Transformed; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D018408:Patch-Clamp Techniques / Q000379:methods; D010406:Penicillins / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D010406:Penicillins; D021122:Protein Subunits; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D011188:Potassium
references.citation: J Neurochem. 2003 Dec;87(6):1444-55
references.pmid: 14713300
references.citation: Mol Pharmacol. 2004 Oct;66(4):988-1003
references.pmid: 15247320
references.citation: Br J Pharmacol. 1992 Nov;107(3):732-7
references.pmid: 1335335
references.citation: J Neurosci. 2004 Sep 29;24(39):8629-39
references.pmid: 15456836
references.citation: J Neurosci. 2007 Jul 11;27(28):7520-31
references.pmid: 17626213
references.citation: Adv Pharmacol. 2006;54:147-69
references.pmid: 17175814
references.citation: J Neurosci. 1994 Nov;14(11 Pt 2):7077-86
references.pmid: 7525894
references.citation: Mol Pharmacol. 1999 Jul;56(1):110-5
references.pmid: 10385690
references.citation: J Neurophysiol. 2003 Feb;89(2):871-83
references.pmid: 12574465
references.citation: J Neurosci. 2004 Sep 29;24(39):8454-8
references.pmid: 15456818
references.citation: J Physiol. 1977 Jan;264(1):89-124
references.pmid: 190384
references.citation: J Physiol. 1957 Aug 29;138(1):63-80
references.pmid: 13463799
references.citation: J Physiol. 2007 Aug 1;582(Pt 3):1163-78
references.pmid: 17525114
references.citation: Neuropharmacology. 1997 Jan;36(1):63-73
references.pmid: 9144642
references.citation: Nature. 1977 Jun 23;267(5613):720-1
references.pmid: 195224
references.citation: Trends Neurosci. 2004 May;27(5):262-9
references.pmid: 15111008
references.citation: Biophys J. 2005 Mar;88(3):1740-54
references.pmid: 15626699
references.citation: J Neurosci. 2006 Feb 8;26(6):1749-58
references.pmid: 16467523
references.citation: J Neurosci. 1998 Mar 1;18(5):1693-703
references.pmid: 9464994
references.citation: Br J Pharmacol. 1986 Jul;88(3):541-7
references.pmid: 2427143
references.citation: J Physiol. 2002 Oct 1;544(Pt 1):3-18
references.pmid: 12356876
references.citation: Trends Neurosci. 1996 Apr;19(4):139-43
references.pmid: 8658597
references.citation: Trends Neurosci. 1996 Mar;19(3):96-101
references.pmid: 9054063
references.citation: Br J Pharmacol. 2000 Jan;129(2):402-8
references.pmid: 10694249
references.citation: Brain Res. 2004 Dec 17;1029(2):207-16
references.pmid: 15542076
references.citation: J Neurophysiol. 2002 May;87(5):2624-8
references.pmid: 11976398
references.citation: Neuropharmacology. 2004 Dec;47(7):945-60
references.pmid: 15555630
references.citation: J Physiol. 1992 Jan;445:97-127
references.pmid: 1323672
references.citation: J Neurosci. 2002 May 15;22(10):RC223
references.pmid: 12006605
references.citation: J Physiol. 1978 May;278:207-35
references.pmid: 671288
references.citation: Brain Res. 1992 Nov 13;595(2):249-55
references.pmid: 1281737
references.citation: J Physiol. 2007 Nov 1;584(Pt 3):769-87
references.pmid: 17884921
references.citation: Neuroscience. 1994 Mar;59(2):259-73
references.pmid: 7911981
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15230-5
references.pmid: 17005728
references.citation: Br J Pharmacol. 2002 Jan;135(2):427-32
references.pmid: 11815378
references.citation: Epilepsy Res. 1996 Nov;25(3):185-90
references.pmid: 8956915
references.citation: Epilepsy Res. 2000 Jan;38(1):33-44
references.pmid: 10604604
references.citation: J Physiol. 1999 Jan 1;514 ( Pt 1):27-45
references.pmid: 9831714
references.citation: J Neurophysiol. 2003 Apr;89(4):1929-40
references.pmid: 12612040
references.citation: Mol Pharmacol. 1996 Mar;49(3):494-504
references.pmid: 8643089
references.citation: Neurochem Res. 1994 Jan;19(1):1-4
references.pmid: 8139755
references.citation: Neuron. 1995 Jul;15(1):181-91
references.pmid: 7542462
references.citation: J Neurosci. 2002 Mar 1;22(5):1541-9
references.pmid: 11880484
references.citation: J Physiol. 2007 Feb 1;578(Pt 3):655-76
references.pmid: 17124266
references.citation: J Physiol. 2006 Apr 1;572(Pt 1):183-200
references.pmid: 16455693
references.citation: J Comp Neurol. 2002 Jan 28;443(1):43-55
references.pmid: 11793346
references.citation: J Physiol. 1978 Apr;277:153-76
references.pmid: 306437
references.citation: J Neurosci. 2003 Nov 19;23(33):10650-61
references.pmid: 14627650
references.citation: Mol Pharmacol. 2004 Dec;66(6):1517-24
references.pmid: 15331770
references.citation: Trends Neurosci. 2004 Sep;27(9):569-75
references.pmid: 15331240
references.citation: J Membr Biol. 1996 Nov;154(1):11-21
references.pmid: 8881023
references.citation: J Physiol. 1978 May;278:237-50
references.pmid: 671293
references.citation: Mol Pharmacol. 2006 Feb;69(2):564-75
references.pmid: 16282519
references.citation: Pharmacol Ther. 2004 Jun;102(3):195-221
references.pmid: 15246246
references.citation: Nat Neurosci. 2007 Jan;10(1):40-8
references.pmid: 17159992
references.citation: Eur J Pharmacol. 2004 Aug 2;496(1-3):23-32
references.pmid: 15288571
references.citation: Nat Neurosci. 1998 Nov;1(7):563-71
references.pmid: 10196563
references.citation: J Physiol. 1977 Jun;268(2):291-318
references.pmid: 301570
references.citation: Mol Pharmacol. 2003 Jan;63(1):2-8
references.pmid: 12488530
references.citation: J Physiol. 1979 Oct;295:139-70
references.pmid: 42780
references.citation: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references.pmid: 15738957
references.citation: Acta Paediatr Taiwan. 2002 Nov-Dec;43(6):313-8
references.pmid: 12632783
references.citation: Nat Rev Drug Discov. 2006 Feb;5(2):160-70
references.pmid: 16424917
references.citation: Neuroscience. 1997 Dec;81(4):1111-22
references.pmid: 9330372
references.citation: J Neurosci. 1992 Mar;12(3):1040-62
references.pmid: 1312131