Charge and geometry of residues in the loop 2 β hairpin differentially affect agonist and ethanol sensitivity in glycine receptors.

The Journal of Pharmacology and Experimental Therapeutics
Daya I PerkinsRonald L Alkana

Abstract

Recent studies highlighted the importance of loop 2 of α1 glycine receptors (GlyRs) in the propagation of ligand-binding energy to the channel gate. Mutations that changed polarity at position 52 in the β hairpin of loop 2 significantly affected sensitivity to ethanol. The present study extends the investigation to charged residues. We found that substituting alanine with the negative glutamate at position 52 (A52E) significantly left-shifted the glycine concentration response curve and increased sensitivity to ethanol, whereas the negative aspartate substitution (A52D) significantly right-shifted the glycine EC₅₀ but did not affect ethanol sensitivity. It is noteworthy that the uncharged glutamine at position 52 (A52Q) caused only a small right shift of the glycine EC₅₀ while increasing ethanol sensitivity as much as A52E. In contrast, the shorter uncharged asparagine (A52N) caused the greatest right shift of glycine EC₅₀ and reduced ethanol sensitivity to half of wild type. Collectively, these findings suggest that charge interactions determined by the specific geometry of the amino acid at position 52 (e.g., the 1-Å chain length difference between aspartate and glutamate) play differential roles in receptor sensitivity to ag...Continue Reading

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Oct 8, 2013·The Protein Journal·Yee Siew ChoongTheam Soon Lim
Dec 12, 2012·The Journal of Pharmacology and Experimental Therapeutics·Lindsay M McCrackenR Adron Harris
May 29, 2014·Trends in Pharmacological Sciences·James R TrudellR Adron Harris
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Jan 16, 2015·The Journal of Pharmacology and Experimental Therapeutics·Andrea SánchezLuis G Aguayo
Apr 29, 2020·Alcoholism, Clinical and Experimental Research·Shoupeng WeiJian-Hui Liang
Oct 30, 2013·Alcoholism, Clinical and Experimental Research·Richard W OlsenDaryl L Davies
Jul 31, 2013·Alcoholism, Clinical and Experimental Research·Lindsay M McCrackenR Adron Harris
May 15, 2015·Alcoholism, Clinical and Experimental Research·Suzzane HoraniRebecca J Howard

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