Reduced Activation of the Synaptic-Type GABA A Receptor Following Prolonged Exposure to Low Concentrations of Agonists: Relationship between Tonic Activity and Desensitization.

التفاصيل البيبلوغرافية
العنوان:	Reduced Activation of the Synaptic-Type GABA A Receptor Following Prolonged Exposure to Low Concentrations of Agonists: Relationship between Tonic Activity and Desensitization.
المؤلفون:	Pierce SR; Department of Anesthesiology (S.R.P., A.L.G., A.S.E., J.H.S., G.A.) and the Taylor Family Institute for Innovative Psychiatric Research (A.S.E., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri., Germann AL; Department of Anesthesiology (S.R.P., A.L.G., A.S.E., J.H.S., G.A.) and the Taylor Family Institute for Innovative Psychiatric Research (A.S.E., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri., Evers AS; Department of Anesthesiology (S.R.P., A.L.G., A.S.E., J.H.S., G.A.) and the Taylor Family Institute for Innovative Psychiatric Research (A.S.E., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri., Steinbach JH; Department of Anesthesiology (S.R.P., A.L.G., A.S.E., J.H.S., G.A.) and the Taylor Family Institute for Innovative Psychiatric Research (A.S.E., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri., Akk G; Department of Anesthesiology (S.R.P., A.L.G., A.S.E., J.H.S., G.A.) and the Taylor Family Institute for Innovative Psychiatric Research (A.S.E., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri akk@morpheus.wustl.edu.
المصدر:	Molecular pharmacology [Mol Pharmacol] 2020 Dec; Vol. 98 (6), pp. 762-769. Date of Electronic Publication: 2020 Sep 25.
نوع المنشور:	Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics
مواضيع طبية MeSH:	GABA-A Receptor Agonists/pharmacology , Receptors, GABA-A/metabolism , Synaptic Potentials/*drug effects, Animals ; Cells, Cultured ; Dose-Response Relationship, Drug ; Humans ; Oocytes ; Patch-Clamp Techniques ; Pregnanolone/pharmacology ; Recombinant Proteins/metabolism ; Time Factors ; Xenopus laevis ; gamma-Aminobutyric Acid/pharmacology
مستخلص:	Synaptic GABA A receptors are alternately exposed to short pulses of a high, millimolar concentration of GABA and prolonged periods of low, micromolar concentration of the transmitter. Prior work has indicated that exposure to micromolar concentrations of GABA can both activate the postsynaptic receptors generating sustained low-amplitude current and desensitize the receptors, thereby reducing the peak amplitude of subsequent synaptic response. However, the precise relationship between tonic activation and reduction of peak response is not known. Here, we have measured the effect of prolonged exposure to GABA or the combination of GABA and the neurosteroid allopregnanolone, which was intended to desensitize a fraction of receptors, on a subsequent response to a high concentration of agonist in human α 1 β 3 γ 2L receptors expressed in Xenopus oocytes. We show that the reduction in the peak amplitude of the post-exposure test response correlates with the open probability of the preceding desensitizing response. Curve fitting of the inhibitory relationship yielded an IC 50 of 12.5 µM and a Hill coefficient of -1.61. The activation and desensitization data were mechanistically analyzed in the framework of a three-state Resting-Active-Desensitized model. Using the estimated affinity, efficacy, and desensitization parameters, we calculated the amount of desensitization that would accumulate during a long (2-minute) application of GABA or GABA plus allopregnanolone. The results indicate that accumulation of desensitization depends on the level of activity rather than agonist or potentiator concentration per se. We estimate that in the presence of 1 µM GABA, approximately 5% of α 1 β 3 γ 2L receptors are functionally eliminated because of desensitization. SIGNIFICANCE STATEMENT: We present an analytical approach to quantify and predict the loss of activatable GABA A receptors due to desensitization in the presence of transmitter and the steroid allopregnanolone. The findings indicate that the peak amplitude of the synaptic response is influenced by ambient GABA and that changes in ambient concentrations of the transmitter and other GABAergic agents can modify tonically and phasically activated synaptic receptors in opposite directions. (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)
References:	J Physiol. 1990 Nov;430:213-49. (PMID: 1707966) Mol Pharmacol. 2019 Sep;96(3):320-329. (PMID: 31263018) J Physiol. 2012 Jan 1;590(1):93-8. (PMID: 21807612) Neuron. 1995 Jul;15(1):181-91. (PMID: 7542462) J Neurosci. 2011 Jan 12;31(2):753-63. (PMID: 21228184) Sci Rep. 2019 Nov 13;9(1):16683. (PMID: 31723152) J Mol Biol. 1965 May;12:88-118. (PMID: 14343300) Mol Pharmacol. 2018 Feb;93(2):178-189. (PMID: 29192122) J Neurosci. 2018 Sep 19;38(38):8128-8145. (PMID: 30076210) Mol Pharmacol. 2019 Jan;95(1):106-119. (PMID: 30333132) Brain Res. 1986 Oct 1;384(1):145-55. (PMID: 3790989) Mol Pharmacol. 2004 Oct;66(4):988-1003. (PMID: 15247320) J Physiol. 2002 Oct 1;544(Pt 1):3-18. (PMID: 12356876) Trends Neurosci. 1996 May;19(5):163-71. (PMID: 8723198) Nature. 1998 Sep 10;395(6698):172-7. (PMID: 9744275) Mol Pharmacol. 2017 Nov;92(5):556-563. (PMID: 28790148) Recept Channels. 1994;2(3):227-36. (PMID: 7874449) Mol Pharmacol. 2018 Feb;93(2):90-100. (PMID: 29150461) J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Jun 15;1055-1056:1-7. (PMID: 28433865) Mol Pharmacol. 2020 Jan;97(1):49-60. (PMID: 31882404) Front Cell Neurosci. 2014 May 13;8:128. (PMID: 24860430) J Neurosci. 1999 Apr 1;19(7):2474-88. (PMID: 10087062) Mol Pharmacol. 1994 Mar;45(3):546-54. (PMID: 8145738) Neuroscience. 2007 Sep 7;148(3):794-805. (PMID: 17693036) Curr Opin Anaesthesiol. 2012 Aug;25(4):411-8. (PMID: 22614249) Sci Rep. 2019 Nov 5;9(1):15997. (PMID: 31690811) Anesthesiology. 2012 Jan;116(1):47-55. (PMID: 22104494) J Physiol. 2002 Jun 1;541(Pt 2):367-83. (PMID: 12042345) J Physiol. 1989 May;412:513-41. (PMID: 2557431) Mol Pharmacol. 2016 Sep;90(3):288-99. (PMID: 27190210) J Neurophysiol. 1996 Dec;76(6):3983-93. (PMID: 8985894) J Neurosci. 1994 Dec;14(12):7747-60. (PMID: 7996209) J Neurosci. 2003 Nov 19;23(33):10650-61. (PMID: 14627650) J Physiol. 2001 Dec 15;537(Pt 3):715-33. (PMID: 11744750) J Neurosci. 2013 Sep 11;33(37):14850-68. (PMID: 24027285) Mol Neurobiol. 2009 Dec;40(3):289-306. (PMID: 19844813) J Neurosci. 2000 Nov 1;20(21):7914-21. (PMID: 11050111) Physiol Rep. 2019 Sep;7(18):e14230. (PMID: 31549483)
معلومات مُعتمدة:	R01 GM108580 United States GM NIGMS NIH HHS; R01 GM108799 United States GM NIGMS NIH HHS
المشرفين على المادة:	0 (GABA-A Receptor Agonists) 0 (Receptors, GABA-A) 0 (Recombinant Proteins) 56-12-2 (gamma-Aminobutyric Acid) BXO86P3XXW (Pregnanolone)
تواريخ الأحداث:	Date Created: 20200926 Date Completed: 20201211 Latest Revision: 20211203
رمز التحديث:	20231215
مُعرف محوري في PubMed:	PMC7673486
DOI:	10.1124/molpharm.120.000088
PMID:	32978327
قاعدة البيانات:	MEDLINE

الوصف
تدمد:	1521-0111
DOI:	10.1124/molpharm.120.000088