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J. Biol. Chem., Vol. 279, Issue 2, 876-883, January 9, 2004

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Molecular Determinants of Proton Modulation of Glycine Receptors^*

Zhenglan Chen, Glenn H. Dillon, and Renqi Huang

From the Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107

Extracellular pH regulates glycine receptors through an unknown mechanism. Here we demonstrate that acidic pH remarkably inhibited glycine-activated whole-cell currents in recombinant glycine 1 and 1 receptors transiently expressed in human embryonic kidney 293 cells. The proton effect was voltage-independent and pharmacologically competed with glycine receptor agonist glycine and antagonist strychnine. Using site-directed mutagenesis, we have identified an N-terminal domain that is essential for proton-induced inhibition of glycine current. In 1 homomers, removal of the hydroxyl group by mutation of residue Thr-112 to Ala or Phe abolished inhibition of glycine currents by acidification. In contrast, mutation of Thr-112 to another hydroxylated residue (Tyr) produced receptors that retained partial proton sensitivity. In 1 heteromers, a single mutation of the subunit T135A, which is homologous to 1 Thr-112, reduced proton sensitivity, whereas the double mutation 1(T112A)(T135A) almost completely eliminated the proton sensitivity. In addition, the mutation 1 H109A greatly reduced sensitivity to protons in homomeric 1 receptors. The results demonstrate that extracellular pH can regulate the function of glycine 1 and 1 receptors. An extracellular domain consisting of Thr-112 and His-109 at the 1 subunit and Thr-135 at the subunit plays a critical role in determining proton modulation of glycine receptor function.

Received for publication, July 16, 2003 , and in revised form, September 29, 2003.

Note Added in Proof—While this paper was under review, Li et al. (Li, Y.-F., Wu, L.-J., Li, Y., Xu, L., and Xu, T.-L. (2003) J. Physiol. (Lond.) 552, 73–87) reported similar proton effects on native glycine receptors.

^* This research was supported by American Heart Association Texas Affiliate Grant 0160091Y (to R. H.), by a Faculty Research Grant from the University of North Texas Health Science Center (to R. H.), and by National Institutes of Health Grant ES07904 (to G. H. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 817-735-2095; Fax: 817-735-2091; E-mail: rhuang{at}hsc.unt.edu.

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