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Molecular Pharmacology

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Research ArticleArticle

Agonist-Induced Conformational Changes in the Extracellular Domain of α7 Nicotinic Acetylcholine Receptors

Lisa K. Lyford, Adrian D. Sproul, Donnie Eddins, James T. McLaughlin and Robert L. Rosenberg
Molecular Pharmacology September 2003, 64 (3) 650-658; DOI: https://doi.org/10.1124/mol.64.3.650
Lisa K. Lyford
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Adrian D. Sproul
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Donnie Eddins
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James T. McLaughlin
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Robert L. Rosenberg
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Abstract

The molecular mechanisms that couple agonist binding to the gating of Cys-loop ionotropic receptors are not well understood. The crystal structure of the acetylcholine (ACh) binding protein has provided insights into the structure of the extracellular domain of nicotinic receptors and a framework for testing mechanisms of activation. Key ligand binding residues are located at the C-terminal end of the β9 strand. At the N-terminal end of this strand (loop 9) is a conserved glutamate [E172 in chick α7 nicotinic acetylcholine receptors (nAChRs)] that is important for modulating activation. We hypothesize that agonist binding induces the movement of loop 9. To test this, we used the substituted-cysteine accessibility method to examine agonist-dependent changes in the modification of cysteines introduced in loop 9 of L247T α7 nAChRs. In the absence of agonist, ACh-evoked responses of E172C/L247T α7 nAChRs were inhibited by 2-trimethylammonioethylmethane thiosulfonate (MTSET). Agonist coapplication with MTSET reduced the extent and rate of modification. The dose-dependence of ACh activation was nearly identical with that of ACh-dependent protection from modification. ACh increased the inhibition by methanethiosulfonate reagents of N170C and did not change inhibition of G171C receptors. The antagonist dihydro-β-erythroidine did not mimic the effects of ACh. Combined with a structural model, the data suggest that receptor activation includes subunit rotation and/or intrasubunit conformational changes that move N170 to a more accessible position and E172 to a more protected position away from the vestibule. Thus, loop 9, located near the junction between the extracellular and transmembrane domains, participates in conformational changes triggered by ligand binding.

  • Received April 2, 2003.
  • Accepted June 17, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 64 (3)
Molecular Pharmacology
Vol. 64, Issue 3
1 Sep 2003
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Research ArticleArticle

Agonist-Induced Conformational Changes in the Extracellular Domain of α7 Nicotinic Acetylcholine Receptors

Lisa K. Lyford, Adrian D. Sproul, Donnie Eddins, James T. McLaughlin and Robert L. Rosenberg
Molecular Pharmacology September 1, 2003, 64 (3) 650-658; DOI: https://doi.org/10.1124/mol.64.3.650

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Research ArticleArticle

Agonist-Induced Conformational Changes in the Extracellular Domain of α7 Nicotinic Acetylcholine Receptors

Lisa K. Lyford, Adrian D. Sproul, Donnie Eddins, James T. McLaughlin and Robert L. Rosenberg
Molecular Pharmacology September 1, 2003, 64 (3) 650-658; DOI: https://doi.org/10.1124/mol.64.3.650
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