Non-agonist-binding subunit interfaces confer distinct functional signatures to the alternate stoichiometries of the α4β2 nicotinic receptor: An α4-α4 interface is required for Zn2+ potentiation

Mirko Moroni, Ranjit Vijayan, Anna Carbone, Ruud Zwart, Philip C. Biggin, Isabel Bermudez

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

Abstract

The α4β2 subtype is the most abundant nicotinic acetylcholine receptor (nAChR) in the brain and possesses the high-affinity binding site for nicotine. The α4 and β2 nAChR subunits assemble into two alternate stoichiometries, (α4)2(β2)3 and (α4) 3(β2)2, which differ in their functional properties and sensitivity to chronic exposure to nicotine. Here, we investigated the sensitivity of both receptor stoichiometries to modulation by Zn2+. We show that Zn2+ exerts an inhibitory modulatory effect on (α4)2(β2)3 receptors, whereas it potentiates or inhibits, depending on its concentration, the function of (α4) 3(β2)2 receptors. Furthermore, Zn2+ inhibition on (α4)2(β2)3 nAChRs is voltage-dependent, whereas it is not on (α4)3(β2) 2 receptors. We used molecular modeling in conjunction with alanine substitution and functional studies to identify two distinct sets of residues that determine these effects and may coordinate Zn2+. Zn2+ inhibition is mediated by a site located on the β2(+)/α4(-) subunit interfaces on both receptor stoichiometries. α4H195 and β2D218 are key determinants of this site. Zn2+ potentiation on (α4)3(β2)2 nAChRs is exerted by a site that resides on the α4(+)/α4(-) of this receptor stoichiometry. α4H195 on the (-) side of the ACh-binding α4 subunit and α4E224 on the (+) side of the non-ACh-binding α4 subunit critically contribute to this site. We also identified residues within the β2 subunit that confer voltage dependency to Zn2+ inhibition on (α4)2(β2)3, but not on (α4)3(β2)2 nAChRs.

Original languageEnglish
Pages (from-to)6884-6894
Number of pages11
JournalJournal of Neuroscience
Volume28
Issue number27
DOIs
Publication statusPublished - Jul 2 2008
Externally publishedYes

Keywords

  • ACh
  • Acetylcholine
  • Nicotinic receptors
  • Subunit interfaces
  • Zn modulation
  • α4β2 receptors

ASJC Scopus subject areas

  • Neuroscience(all)

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