2. Academic Validation
  3. Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors

Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors

  • Biochem Pharmacol. 2014 Oct 15;91(4):534-42. doi: 10.1016/j.bcp.2014.07.025.
Gene Hopping 1,  C-I Anderson Wang 1,  Ron C Hogg 2,  Simon T Nevin 3,  Richard J Lewis 1,  David J Adams 4,  Paul F Alewood 5
Affiliations

Affiliations

  • 1 Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • 2 Department of Neuroscience, Centre Medical Universitaire, Medical Faculty, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland.
  • 3 Queensland Brain Institute, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • 4 Queensland Brain Institute, The University of Queensland, St. Lucia, Queensland 4072, Australia; Health Innovations Research Institute, RMIT University, Bundoora, Victoria 3083, Australia.
  • 5 Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia. Electronic address: [email protected].
PMID: 25101833 DOI: 10.1016/j.bcp.2014.07.025
Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are a diverse class of ligand-gated ion channels involved in neurological conditions such as neuropathic pain and Alzheimer's disease. α-Conotoxin [A10L]PnIA is a potent and selective antagonist of the mammalian α7 nAChR with a key binding interaction at position 10. We now describe a molecular analysis of the receptor-ligand interactions that determine the role of position 10 in determining potency and selectivity for the α7 and α3β2 nAChR subtypes. Using electrophysiological and radioligand binding methods on a suite of [A10L]PnIA analogs we observed that hydrophobic residues in position 10 maintained potency at both subtypes whereas charged or polar residues abolished α7 binding. Molecular docking revealed dominant hydrophobic interactions with several α7 and α3β2 receptor residues via a hydrophobic funnel. Incorporation of norleucine (Nle) caused the largest (8-fold) increase in affinity for the α7 subtype (Ki=44nM) though selectivity reverted to α3β2 (IC50=0.7nM). It appears that the placement of a single methyl group determines selectivity between α7 and α3β2 nAChRs via different molecular determinants.

Keywords

Alpha-conotoxin; Nicotinic acetylcholine receptors; Structure–function relationship.

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