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Title: 2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA A-ρ1 Receptors

All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABA(C)R (GABA(A)-rho), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABA(C)R versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABA(C)R(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABA(C)R antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABA(A)R antagonist, SR95531; GABA(B)R antagonist, CGP, and agonist, baclofen. Intravitreal injections of TPMPA and SR95531 were also made in Brown Norway rats. The effect of 2-AEMP on GABA-induced current was tested directly in isolated rat rod bipolar cells, and 2-AEMP was found to preferentially block GABA(C)R in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABA(C)R(-/-) mice, compared to B6 mice, by 30-60%; a-waves were unaltered and oscillatory potential amplitudes were increased. In B6 mice, after injection of TPMPA (also in rats), 3-APMPA or 2-AEMP, ERGs became similar to ERGs of GABA(C)R(-/-) mice. Blockade of GABA(A)Rs and GABA(B)Rs, or agonism of GABA(B)Rs did not alter B6 DA b-wave amplitude. The negative scotopic thresholdmore » response (nSTR) was slightly less sensitive in GABA(C)R(-/-) than in B6 mice, and unaltered by 2-AEMP. However, amplitudes of nSTR and photopic negative response (PhNR), both of which originate from inner retina, were enhanced by TPMPA and 3-APMPA, each of which has GABA(B) agonist properties, and further increased by baclofen. The finding that genetic deletion of GABA(C)R, the GABA(C)R antagonist 2-AEMP, and other antagonists all reduced ERG b-wave amplitude, supports a role for CABA(C)R in determining the maximum response amplitude of bipolar cells contributing to the b-wave. GABA(C)R antagonists differed in their effects on nSTR and PhNR; antagonists with GABA(B) agonist properties enhanced light-driven responses whereas 2-AEMP did not.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [3] ;  [3] ;  [1] ;  [2] ;  [1] ;  [1]
  1. Univ. of Illinois, Chicago, IL (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  3. Univ. of Sydney, NSW (Australia)
Publication Date:
Grant/Contract Number:
AC05-00OR22725
Type:
Accepted Manuscript
Journal Name:
Molecular Pharmacology
Additional Journal Information:
Journal Volume: 80; Journal Issue: 6; Journal ID: ISSN 0026-895X
Publisher:
American Society for Pharmacology and Experimental Therapeutics
Research Org:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
Work for Others (WFO)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; neurotransmitter; GABA; structure-activity relationships; pharmacology; ion channel
OSTI Identifier:
1334416

Xie, A., Yan, J., Yue, L., Feng, F., Mir, F., Abdel-Halim, H., Chebib, M., Le Breton, G. C., Standaert, R. F., Qian, H., and Pepperberg, D. R.. 2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors. United States: N. p., Web. doi:10.1124/mol.111.071225.
Xie, A., Yan, J., Yue, L., Feng, F., Mir, F., Abdel-Halim, H., Chebib, M., Le Breton, G. C., Standaert, R. F., Qian, H., & Pepperberg, D. R.. 2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors. United States. doi:10.1124/mol.111.071225.
Xie, A., Yan, J., Yue, L., Feng, F., Mir, F., Abdel-Halim, H., Chebib, M., Le Breton, G. C., Standaert, R. F., Qian, H., and Pepperberg, D. R.. 2011. "2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors". United States. doi:10.1124/mol.111.071225. https://www.osti.gov/servlets/purl/1334416.
@article{osti_1334416,
title = {2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors},
author = {Xie, A. and Yan, J. and Yue, L. and Feng, F. and Mir, F. and Abdel-Halim, H. and Chebib, M. and Le Breton, G. C. and Standaert, R. F. and Qian, H. and Pepperberg, D. R.},
abstractNote = {All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABA(C)R (GABA(A)-rho), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABA(C)R versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABA(C)R(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABA(C)R antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABA(A)R antagonist, SR95531; GABA(B)R antagonist, CGP, and agonist, baclofen. Intravitreal injections of TPMPA and SR95531 were also made in Brown Norway rats. The effect of 2-AEMP on GABA-induced current was tested directly in isolated rat rod bipolar cells, and 2-AEMP was found to preferentially block GABA(C)R in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABA(C)R(-/-) mice, compared to B6 mice, by 30-60%; a-waves were unaltered and oscillatory potential amplitudes were increased. In B6 mice, after injection of TPMPA (also in rats), 3-APMPA or 2-AEMP, ERGs became similar to ERGs of GABA(C)R(-/-) mice. Blockade of GABA(A)Rs and GABA(B)Rs, or agonism of GABA(B)Rs did not alter B6 DA b-wave amplitude. The negative scotopic threshold response (nSTR) was slightly less sensitive in GABA(C)R(-/-) than in B6 mice, and unaltered by 2-AEMP. However, amplitudes of nSTR and photopic negative response (PhNR), both of which originate from inner retina, were enhanced by TPMPA and 3-APMPA, each of which has GABA(B) agonist properties, and further increased by baclofen. The finding that genetic deletion of GABA(C)R, the GABA(C)R antagonist 2-AEMP, and other antagonists all reduced ERG b-wave amplitude, supports a role for CABA(C)R in determining the maximum response amplitude of bipolar cells contributing to the b-wave. GABA(C)R antagonists differed in their effects on nSTR and PhNR; antagonists with GABA(B) agonist properties enhanced light-driven responses whereas 2-AEMP did not.},
doi = {10.1124/mol.111.071225},
journal = {Molecular Pharmacology},
number = 6,
volume = 80,
place = {United States},
year = {2011},
month = {8}
}