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Research ArticleNeuropharmacology

Amiloride and GMQ Allosteric Modulation of the GABA-A ρ1 Receptor: Influences of the Intersubunit Site

Heather D. Snell and Eric B. Gonzales
Journal of Pharmacology and Experimental Therapeutics June 2015, 353 (3) 551-559; DOI: https://doi.org/10.1124/jpet.115.222802
Heather D. Snell
Department of Pharmacology and Neuroscience (H.D.S., E.B.G.), Institute for Aging and Alzheimer’s Disease Research (E.B.G.), and Cardiovascular Research Institute (E.B.G.), University of North Texas Health Science Center, Fort Worth, Texas
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Eric B. Gonzales
Department of Pharmacology and Neuroscience (H.D.S., E.B.G.), Institute for Aging and Alzheimer’s Disease Research (E.B.G.), and Cardiovascular Research Institute (E.B.G.), University of North Texas Health Science Center, Fort Worth, Texas
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Abstract

Amiloride, a diuretic used in the treatment of hypertension and congestive heart failure, and 2-guanidine-4-methylquinazoline (GMQ) are guanidine compounds that modulate acid-sensing ion channels. Both compounds have demonstrated affinity for a variety of membrane proteins, including members of the Cys-loop family of ligand-gated ion channels, such as the heteromeric GABA-A αβγ receptors. The actions of these guanidine compounds on the homomeric GABA-A ρ1 receptor remains unclear, especially in light of how many GABA-A αβγ receptor modulators have different effects in the GABA-A ρ1 receptors. We sought to characterize the influence of amiloride and GMQ on the human GABA-A ρ1 receptors using whole-cell patch-clamp electrophysiology. The diuretic amiloride potentiated the human GABA-A ρ1 GABA-mediated current, whereas GMQ antagonized the receptor. Furthermore, a GABA-A second transmembrane domain site, the intersubunit site, responsible for allosteric modulation in the heteromeric GABA-A receptors mediated amiloride’s positive allosteric actions. In contrast, the mutation did not remove GMQ antagonism but only changed the guanidine compound’s potency within the human GABA-A ρ1 receptor. Through modeling and introduction of point mutations, we propose that the GABA-A ρ1 intersubunit site plays a role in mediating the allosteric effects of amiloride and GMQ.

Footnotes

    • Received January 9, 2015.
    • Accepted March 31, 2015.
  • H.D.S. is supported by a training grant from the National Institutes of Health National Institute on Aging [Grant T32-AG020494]. This study was supported by the Welch Foundation [Grant BK-1736]; and the American Heart Association [Beginning Grant-In-Aid Grant 12BGIA8820001].

  • This work was presented at the following workshops: Snell HD and Gonzales EB (2014) Amiloride and GMQ allosteric modulation of the GABA-A ρ1 receptor: influences of the intersubunit site. University of North Texas Health Science Center 21st annual Research Appreciation Day; 2014 Apr 12; Fort Worth, TX; Snell HD and Gonzales EB (2014) Amiloride and GMQ allosteric modulation of the GABA-A ρ1 receptor: influences of the intersubunit site. Experimental Biology (EB) National Conference; 2014 Apr 26–30; San Diego, CA; Snell HD and Gonzales EB (2014) Amiloride and GMQ allosteric modulation of the GABA-A ρ1 receptor: influences of the intersubunit site. Society for the Advancement of Chicanos and Native Americans in Science (SACNAS) National Conference; 2014 Oct 16–18; Los Angeles, CA; and Snell HD and Gonzales EB (2014) Amiloride and GMQ allosteric modulation of the GABA-A ρ1 receptor: influences of the intersubunit site. Society for Neuroscience (SFN) National Conference; 2014 Nov 15–19; Washington, DC.

  • dx.doi.org/10.1124/jpet.115.222802.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 353 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 353, Issue 3
1 Jun 2015
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Research ArticleNeuropharmacology

GABA-A ρ1 Receptor Intersubunit Site Ligands

Heather D. Snell and Eric B. Gonzales
Journal of Pharmacology and Experimental Therapeutics June 1, 2015, 353 (3) 551-559; DOI: https://doi.org/10.1124/jpet.115.222802

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Research ArticleNeuropharmacology

GABA-A ρ1 Receptor Intersubunit Site Ligands

Heather D. Snell and Eric B. Gonzales
Journal of Pharmacology and Experimental Therapeutics June 1, 2015, 353 (3) 551-559; DOI: https://doi.org/10.1124/jpet.115.222802
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