title: Context dependent benzodiazepine modulation of GABA(A) receptor opening frequency.
abstract: The anxiolytic, hypnotic, and anti-convulsant properties of benzodiazepines (BDZs) require modulation of distinct GABA(A) receptor alpha-subtypes. BDZ modulation of GABA(A) receptors is often described in terms of increased opening frequency, and contrasted with the increased open durations occurring with barbiturate modulation. Several studies spanning single channel, rapid kinetic, and whole cell techniques have suggested that BDZs effect this observed change in frequency through increased affinity for GABA. BDZ-sensitive αβγ isoforms exist at extrasynaptic as well as synaptic locations, where they encounter markedly different concentration and time-course of GABA exposure. Interestingly, this affinity-based mechanism (specifically, decreasing the GABA unbinding rate) is only predicted to increase opening frequency under conditions that allow the unbinding and rebinding cycles typical of prolonged exposure to low GABA concentrations, which are more likely to occur at extrasynaptic GABA(A) receptors. In contrast, when rebinding is less likely, such as may occur in certain synaptic conditions, the number, but not the frequency, of channel openings increases in response to BDZ modulation. In conclusion, not only can multiple kinetic mechanisms alter channel opening frequency, but a single mechanism - increased affinity - impacts opening frequency differently under different contexts of GABA(A) receptor activation.
authors.affiliation: Neurology Department, Sleep Division, Massachusetts General Hospital, Wang 720, Boston, MA, 02114, USA. mtbianchi@partners.org
authors.forename: Matt T
authors.initials: MT
authors.lastname: Bianchi
references.citation: J Neurosci. 1998 Nov 1;18(21):8590-604
references.pmid: 9786967
references.citation: Br J Pharmacol. 1998 Nov;125(5):924-47
references.pmid: 9846630
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: J Neurosci. 2001 Dec 1;21(23):9083-91
references.pmid: 11717341
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3674-9
references.pmid: 14990800
references.citation: Eur J Neurosci. 2000 Mar;12(3):810-8
references.pmid: 10762310
references.citation: Neuron. 2007 Dec 6;56(5):763-70
references.pmid: 18054854
references.citation: Nature. 1999 Oct 21;401(6755):796-800
references.pmid: 10548105
references.citation: J Neurosci. 2004 Jul 28;24(30):6785-90
references.pmid: 15282283
references.citation: J Physiol. 1989 Oct;417:483-500
references.pmid: 2482885
references.citation: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references.pmid: 15738957
references.citation: J Neurophysiol. 2003 Feb;89(2):871-83
references.pmid: 12574465
references.citation: J Neurosci. 1999 Jan 15;19(2):578-88
references.pmid: 9880578
references.citation: Proc Natl Acad Sci U S A. 2001 May 22;98(11):6464-9
references.pmid: 11353839
references.citation: Anesthesiology. 2005 Apr;102(4):783-92
references.pmid: 15791108
references.citation: Mol Pharmacol. 2007 Feb;71(2):483-93
references.pmid: 17108261
references.citation: Neuropharmacology. 1996;35(9-10):1383-92
references.pmid: 9014155
references.citation: Trends Neurosci. 2004 May;27(5):262-9
references.pmid: 15111008
references.citation: J Neurosci. 2002 Jul 1;22(13):5321-7
references.pmid: 12097483
references.citation: Prog Biophys Mol Biol. 2005 Jan;87(1):33-46
references.pmid: 15471589
references.citation: Nature. 1977 Sep 22;269(5626):342-4
references.pmid: 561893
references.citation: Nature. 1978 Feb 9;271(5645):563-4
references.pmid: 563985
references.citation: J Neurophysiol. 2002 May;87(5):2624-8
references.pmid: 11976398
references.citation: Neuroreport. 1999 Mar 17;10(4):817-21
references.pmid: 10208554
references.citation: Mol Pharmacol. 2000 Nov;58(5):1129-36
references.pmid: 11040062
references.citation: Br J Pharmacol. 1999 Jul;127(6):1349-58
references.pmid: 10455284
references.citation: Science. 2000 Oct 6;290(5489):131-4
references.pmid: 11021797
references.citation: Eur J Neurosci. 2006 May;23(9):2495-504
references.pmid: 16706856
references.citation: Results Probl Cell Differ. 2008;44:29-48
references.pmid: 17671772
references.citation: J Physiol. 2007 Nov 1;584(Pt 3):769-87
references.pmid: 17884921
references.citation: Epilepsy Res. 2009 Aug;85(2-3):212-20
references.pmid: 19447010
references.citation: J Neurosci. 2005 Aug 31;25(35):8056-65
references.pmid: 16135763
references.citation: Br J Pharmacol. 2000 Apr;129(8):1794-800
references.pmid: 10780988
references.citation: Br J Pharmacol. 2000 Dec;131(7):1251-4
references.pmid: 11090095
references.citation: J Physiol. 1999 Jan 1;514 ( Pt 1):27-45
references.pmid: 9831714
references.citation: Ann Neurol. 1989 Mar;25(3):213-20
references.pmid: 2471436
references.citation: Neuron. 1995 Jul;15(1):181-91
references.pmid: 7542462
references.citation: J Physiol. 2007 Feb 1;578(Pt 3):655-76
references.pmid: 17124266
references.citation: Eur J Neurosci. 2003 May;17(10):2226-30
references.pmid: 12786990
references.citation: Sleep Med Rev. 2005 Dec;9(6):477-87
references.pmid: 16233983
references.citation: Neuropharmacology. 1996;35(9-10):1169-79
references.pmid: 9014132
references.citation: Neuropharmacology. 2001 Nov;41(6):737-44
references.pmid: 11640928
references.citation: Biophys J. 2001 Mar;80(3):1251-61
references.pmid: 11222289
references.citation: J Physiol. 2007 Nov 15;585(Pt 1):29-46
references.pmid: 17855751
references.citation: J Physiol. 2001 Dec 15;537(Pt 3):715-33
references.pmid: 11744750
references.citation: Trends Neurosci. 2004 Sep;27(9):569-75
references.pmid: 15331240
references.citation: Br J Pharmacol. 2005 Aug;145(7):894-906
references.pmid: 15912137
references.citation: Neuroreport. 2007 May 28;18(8):781-5
references.pmid: 17471066
references.citation: Brain Res Brain Res Rev. 1999 Apr;29(2-3):196-217
references.pmid: 10209232
references.citation: Pharmacol Ther. 2006 Dec;112(3):612-29
references.pmid: 16876255
references.citation: J Physiol. 1994 Feb 15;475(1):69-82
references.pmid: 7514665
references.citation: Neuropharmacology. 2009 Jan;56(1):161-73
references.pmid: 18775733
references.citation: Mol Pharmacol. 1999 Jan;55(1):168-78
references.pmid: 9882711
references.citation: J Neurosci. 2000 Nov 1;20(21):7914-21
references.pmid: 11050111
references.citation: Br J Pharmacol. 2006 Aug;148(7):984-90
references.pmid: 16783415