Different binding modes of tropeines mediating inhibition and potentiation of α1 glycine receptors

Gábor Maksay, Bodo Laube, Rudolf Schemm, Joanna Grudzinska, Malgorzata Drwal, Heinrich Betz

Research output: Contribution to journalArticle

16 Citations (Scopus)


Tropeines are bidirectional modulators of native and recombinant glycine receptors (GlyRs) and promising leads for the development of novel modulatory agents. Tropisetron potentiates and inhibits agonist-triggered GlyR currents at femto- to nanomolar and micromolar concentrations respectively. Here, the potentiating and inhibitory effects of another tropeine, 3α-(3′- methoxy-benzoyloxy)nortropane (MBN) were examined by voltage-clamp electrophysiology at wild type and mutant α1 GlyRs expressed in Xenopus laevis oocytes. Several substitutions around the agonist-binding cavity of the α1 subunit interface (N46C, F63A, N102A, R119K, R131A, E157C, K200A, Y202L and F207A) were found to reduce or eliminate MBN inhibition of glycine activation. In contrast, the binding site mutations Q67A, R119A and S129A which did not affect MBN inhibition abolished the potentiation of chloride currents elicited by low concentrations of the partial agonist taurine following pre-incubation with MBN. Thus, potentiation and inhibition involve distinct binding modes of MBN in the inter-subunit agonist-binding pocket of α1 GlyRs. Homology modelling and molecular dynamics simulations disclosed two distinct docking modes for MBN, which are consistent with the differential effects of individual binding site substitutions on MBN inhibition and potentiation respectively. Together these results suggest that distinct binding modes at adjacent binding sites located within the agonist-binding pocket of the GlyR mediate the bidirectional modulatory effects of tropeines.

Original languageEnglish
Pages (from-to)1725-1732
Number of pages8
JournalJournal of neurochemistry
Issue number6
Publication statusPublished - Jun 1 2009


  • Inhibition
  • Ligand docking
  • Molecular dynamics simulation
  • Potentiation
  • Tropeine binding
  • α1 glycine receptors

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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