Amiloride and GMQ Allosteric Modulation of the GABA-A ρ1 Receptor: Influences of the Intersubunit Site
Autor: | Eric B. Gonzales, Heather D. Snell |
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Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Models
Molecular Patch-Clamp Techniques Allosteric regulation Molecular Sequence Data Pharmacology Guanidines Amiloride chemistry.chemical_compound Neuropharmacology medicine Homomeric Humans Patch clamp Amino Acid Sequence Guanidine Receptor Diuretics Ion channel Cells Cultured GABAA receptor Receptors GABA-A chemistry nervous system Histamine H2 Antagonists Biophysics Mutagenesis Site-Directed Quinazolines Molecular Medicine medicine.drug |
Popis: | 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. |
Databáze: | OpenAIRE |
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