TY - JOUR T1 - Activated G Protein α<sub>s</sub> Subunits Increase the Ethanol Sensitivity of Human Glycine Receptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 386 LP - 393 DO - 10.1124/jpet.111.184408 VL - 339 IS - 2 AU - Gonzalo E. Yévenes AU - Gustavo Moraga-Cid AU - Ximena Romo AU - Luis G. Aguayo Y1 - 2011/11/01 UR - http://jpet.aspetjournals.org/content/339/2/386.abstract N2 - It is well known that ethanol modulates the function of the Cys loop ligand-gated ion channels, which include the inhibitory glycine receptors (GlyRs). Previous studies have consistently shown that transmembrane and extracellular sites are essential for ethanol actions in GlyRs. In addition, recent evidence has shown that the ethanol modulation of GlyRs is also affected by G protein activation through Gβγ subunits. However, more specific roles of G protein α subunits on ethanol actions are unknown. Here, we show that the allosteric effect of ethanol on the human α1 GlyR is selectively enhanced by the expression of Gαs Q-L. For example, constitutively active Gαs, but not Gαq or Gαi, was able to displace the alcohol sensitivity of GlyRs toward low millimolar concentrations (17 ± 4 versus 48 ± 5% at 100 mM). Experiments under conditions that increased cAMP and protein kinase A (PKA)-mediated signaling, on the contrary, did not produce the same enhancement in sensitivity, suggesting that the Gαs Q-L effect was not dependent on cAMP/PKA-dependent signaling. On the other hand, the effect of Gαs Q-L was blocked by a Gβγ scavenger (9 ± 3% of control). Furthermore, two mutant receptors previously shown to have impaired interactions with Gβγ were not affected by Gαs Q-L, suggesting that Gβγ is needed for enhancing ethanol sensitivity. These results support the conclusion that activated Gαs can facilitate the Gβγ interaction with GlyRs in presence of ethanol, independent of increases in cAMP signaling. Thus, these data indicate that the activated form of Gαs is able to positively influence the effect of ethanol on a type of inhibitory receptor important for motor control, pain, and respiration. ER -