Agonist Gating and Isoflurane Potentiation in the Human γ-Aminobutyric Acid Type A Receptor Determined by the Volume of a Second Transmembrane Domain Residue

• DOI: 10.1124/mol.56.5.1087
• Publication Date: 2018-01-08T20:37:23Z
• Authors: Vladimir V. Koltc...; Suzanne E. Finn; Andrew Jenkins; Natalia Nikolaeva; Audrey Lin; Neil L. Harrison
• Keywords: Aminobutyric acid; Residue (chemistry); GABA receptor

γ-Aminobutyric acid type A (GABA_A )receptors are targets for allosteric modulation by general anesthetics. Mutation of Ser270 within the second transmembrane domain GABA_Areceptor α subunit can ablate receptor anesthetic ether isoflurane. To investigate further function this critical amino residue, we made multiple substitutions at and analyzed concentration-dependent gating GABA regulation isoflurane in each mutant receptor. There is a strong negative correlation between EC₅₀ molecular volume residue position 270. Replacement Ser large residues such as His Trp produced shift concentration-response curve to left, whereas replacement with Gly had opposite effect. also was association 270 degree enhancement submaximal responses These results indicate significance α270 GABA_Areceptor. In addition, data on consistent existence cavity finite size region that may be filled molecule or side chain larger α270. The introduction isoflurane, into stabilize open state GABA_A relative closed state.