1. Academic Validation
  2. Molecular determinants of subtype-selective efficacies of cytisine and the novel compound NS3861 at heteromeric nicotinic acetylcholine receptors

Molecular determinants of subtype-selective efficacies of cytisine and the novel compound NS3861 at heteromeric nicotinic acetylcholine receptors

  • J Biol Chem. 2013 Jan 25;288(4):2559-70. doi: 10.1074/jbc.M112.436337.
Kasper Harpsøe 1 Helle Hald Daniel B Timmermann Marianne L Jensen Tino Dyhring Elsebet Ø Nielsen Dan Peters Thomas Balle Michael Gajhede Jette S Kastrup Philip K Ahring
Affiliations

Affiliation

  • 1 Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Abstract

Deciphering which specific agonist-receptor interactions affect efficacy levels is of high importance, because this will ultimately aid in designing selective drugs. The novel compound NS3861 and cytisine are agonists of nicotinic acetylcholine receptors (nAChRs) and both bind with high affinity to heteromeric α3β4 and α4β2 nAChRs. However, initial data revealed that the activation patterns of the two compounds show very distinct maximal efficacy readouts at various heteromeric nAChRs. To investigate the molecular determinants behind these observations, we performed in-depth patch clamp electrophysiological measurements of efficacy levels at heteromeric combinations of α3- and α4-, with β2- and β4-subunits, and various chimeric constructs thereof. Compared with cytisine, which selectively activates receptors containing β4- but not β2-subunits, NS3861 displays the opposite β-subunit preference and a complete lack of activation at α4-containing receptors. The maximal efficacy of NS3861 appeared solely dependent on the nature of the ligand-binding domain, whereas efficacy of cytisine was additionally affected by the nature of the β-subunit transmembrane domain. Molecular docking to nAChR subtype homology models suggests agonist specific interactions to two different residues on the complementary subunits as responsible for the β-subunit preference of both compounds. Furthermore, a principal subunit serine to threonine substitution may explain the lack of NS3861 activation at α4-containing receptors. In conclusion, our results are consistent with a hypothesis where agonist interactions with the principal subunit (α) primarily determine binding affinity, whereas interactions with key Amino acids at the complementary subunit (β) affect agonist efficacy.

Figures
Products
我们的 Cookie 政策

我们使用 Cookies 和类似技术以提高网站的性能和提升您的浏览体验,部分功能也使用 Cookies 帮助我们更好地理解您的需求,为您提供相关的服务。 如果您有任何关于我们如何处理您个人信息的疑问,请阅读我们的《隐私声明》