Publications: Peer-reviewed journal articles (by staff)

Comparison of acetylcholine receptor interactions of the marine toxins, 13-desmethylspirolide C and gymnodimine

  • Hauser TA,
  • Hepler CA,
  • Kombo DC,
  • Grinevich VP,
  • Kiser M,
  • Hooker DN,
  • Zhang J,
  • Mountfort D,
  • Selwood AI,
  • Akireddy SR,
  • Letchworth SR,
  • and Yohannes D
1 January, 2012
CITATION

Hauser TA, Hepler CA, Kombo DC, Grinevich VP, Kiser M, Hooker DN, Zhang J, Mountfort D, Selwood A, Akireddy SR, Letchworth SR, Yohannes D 2012. Comparison of acetylcholine receptor interactions of the marine toxins, 13-desmethylspirolide C and gymnodimine. Neuropharmacology 62(7): 2239-2250

ABSTRACT

The interaction of 13-desmethylspirolide C (SPX-desMe-C) and gymnodimine with several nicotinic and muscarinic acetylcholine receptors was investigated. Interaction at the muscarinic receptors was minimal. At nicotinic receptors, both SPX-desMe-C and gymnodimine displayed greatest affinity for the alpha 7 receptor. The rank order for binding affinity (Ki) for SPX-desMe-C was alpha 7 > alpha 6 beta 3 beta 4 alpha 5 >> rat alpha 3 beta 4, alpha 1 beta gamma delta > alpha 4 beta 4, human alpha 3 beta 4 > human alpha 4 beta 2 > rat alpha 4 beta 2 and for gymnodimine was alpha 7, alpha 6 beta 3 beta 4 alpha 5 > rat alpha 3 beta 4 > human alpha 3 beta 4, alpha 4 beta 4 > rat alpha 4 beta 2, human alpha 4 beta 2 > alpha 1 beta gamma delta. Both molecules antagonized agonist-induced nicotinic responses. The antagonism rank order of potency (IC50) for SPX-desMe-C was alpha 7 > low sensitivity (LS) alpha 4 beta 2 > human alpha 3 beta 4 > high sensitivity (HS) alpha 4 beta 2, alpha 1 beta gamma delta > alpha 4 beta 4 > rat alpha 3 beta 4 and for gymnodimine was LS alpha 4 beta 2 > human alpha 3 beta 4 > alpha 7 > HS alpha 4 beta 2 > alpha 4 beta 4 > rat alpha 3 beta 4 > alpha 1 beta gamma delta. Neither gymnodimine nor SPX-desMe-C antagonism could be surmounted by increasing concentrations of nicotine. To elucidate the nature of this insurmountable blockade, we carried out homology modelling and molecular docking studies of both ligands with alpha 7 nAChR. Their very high binding affinity results from very tight hydrophobic enclosures, in addition to previously reported hydrogen-bond and cation-pi interactions. Also, the higher the hydrophilic surface area of the binding site of nAChRs, the weaker the binding affinity of both ligands. Together these results show the targets of action are nicotinic and define these marine toxins as additional tools to advance our understanding regarding interactions between antagonists and the nAChR ligand binding domain.

(C) 2012 Elsevier Ltd. All rights reserved.