BACKGROUND: Behavioral and biochemical studies indicate that exposure to 12 times normal atmospheric pressure (12 ATA) of helium-oxygen gas (heliox) is a direct, selective ethanol antagonist. The current study begins to test the hypothesis that ethanol acts by a common mechanism on ligand-gated ion channels by expanding previous hyperbaric investigations on gamma-aminobutyric acid type A (GABA(A)) receptors (GABA(A)Rs) at the biochemical level to alpha(1)glycine (GlyRs) expressed in Xenopus oocytes. METHODS: Oocytes expressing wild-type alpha(1) homomeric GlyRs were voltage-clamped (-70 mV) and tested in the presence of glycine (EC(2)) +/- ethanol (50-200 mM) under 1 ATA control and 3 to 12 ATA heliox conditions. Glycine concentration response curves, strychnine/glycine interactions, and zinc (Zn2+) modulation of GlyR function was also tested. RESULTS: Pressure reversibly antagonized the action of ethanol. The degree of antagonism increased as pressure increased. Pressure did not significantly alter the effects of glycine, strychnine, or Zn2+, indicating that ethanol antagonism by pressure cannot be attributed to alterations by pressure of normal GlyR function. The antagonism did not reflect tolerance to ethanol, receptor desensitization, or receptor rundown. CONCLUSION: This is the first use of hyperbarics to investigate the mechanism of action of ethanol in recombinant receptors. The findings indicate that pressure directly and selectively antagonizes ethanol potentiation of alpha(1)GlyR function in a reversible and concentration- and pressure-dependent manner. The sensitivity of ethanol potentiation of GlyR function to pressure antagonism indicates that ethanol acts by a common, pressure-antagonism-sensitive mechanism in GlyRs and GABA(A)Rs. The findings also support the hypothesis that ethanol potentiation of GlyR function plays a role in mediating the sedative-hypnotic effects of ethanol.
BACKGROUND: Behavioral and biochemical studies indicate that exposure to 12 times normal atmospheric pressure (12 ATA) of helium-oxygen gas (heliox) is a direct, selective ethanol antagonist. The current study begins to test the hypothesis that ethanol acts by a common mechanism on ligand-gated ion channels by expanding previous hyperbaric investigations on gamma-aminobutyric acid type A (GABA(A)) receptors (GABA(A)Rs) at the biochemical level to alpha(1)glycine (GlyRs) expressed in Xenopus oocytes. METHODS: Oocytes expressing wild-type alpha(1) homomeric GlyRs were voltage-clamped (-70 mV) and tested in the presence of glycine (EC(2)) +/- ethanol (50-200 mM) under 1 ATA control and 3 to 12 ATA heliox conditions. Glycine concentration response curves, strychnine/glycine interactions, and zinc (Zn2+) modulation of GlyR function was also tested. RESULTS: Pressure reversibly antagonized the action of ethanol. The degree of antagonism increased as pressure increased. Pressure did not significantly alter the effects of glycine, strychnine, or Zn2+, indicating that ethanol antagonism by pressure cannot be attributed to alterations by pressure of normal GlyR function. The antagonism did not reflect tolerance to ethanol, receptor desensitization, or receptor rundown. CONCLUSION: This is the first use of hyperbarics to investigate the mechanism of action of ethanol in recombinant receptors. The findings indicate that pressure directly and selectively antagonizes ethanol potentiation of alpha(1)GlyR function in a reversible and concentration- and pressure-dependent manner. The sensitivity of ethanol potentiation of GlyR function to pressure antagonism indicates that ethanol acts by a common, pressure-antagonism-sensitive mechanism in GlyRs and GABA(A)Rs. The findings also support the hypothesis that ethanol potentiation of GlyR function plays a role in mediating the sedative-hypnotic effects of ethanol.
Authors: Daya I Perkins; James R Trudell; Liana Asatryan; Daryl L Davies; Ronald L Alkana Journal: J Pharmacol Exp Ther Date: 2012-02-22 Impact factor: 4.030
Authors: Daya I Perkins; James R Trudell; Daniel K Crawford; Liana Asatryan; Ronald L Alkana; Daryl L Davies Journal: J Biol Chem Date: 2009-08-05 Impact factor: 5.157
Authors: Rebecca J Howard; Paul A Slesinger; Daryl L Davies; Joydip Das; James R Trudell; R Adron Harris Journal: Alcohol Clin Exp Res Date: 2011-06-15 Impact factor: 3.455
Authors: Anna Naito; Karan H Muchhala; Liana Asatryan; James R Trudell; Gregg E Homanics; Daya I Perkins; Daryl L Davies; Ronald L Alkana Journal: Mol Pharmacol Date: 2014-09-22 Impact factor: 4.436
Authors: A Naito; K H Muchhala; J Trang; L Asatryan; J R Trudell; G E Homanics; R L Alkana; D L Davies Journal: Neuroscience Date: 2015-03-28 Impact factor: 3.590
Authors: Daya I Perkins; James R Trudell; Daniel K Crawford; Ronald L Alkana; Daryl L Davies Journal: Pharmacol Ther Date: 2010-04-23 Impact factor: 12.310