Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition

Kachel, Hamid S.; Patel, Rohit N.; Franzyk, Henrik; Mellor, Ian R.

Abstract

Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 inhibits several excitatory ligand-gated ion channels, and to improve selectivity two synthetic analogues, PhTX-343 and PhTX-12, were developed. Previous work showed a 22-fold selectivity of PhTX-12 over PhTX-343 for embryonic muscle-type nicotinic acetylcholine receptors (nAChRs) in TE671 cells. We investigated their inhibition of different neuronal nAChR subunit combinations as well as of embryonic muscle receptors expressed in Xenopus oocytes. Whole-cell currents in response to application of acetylcholine alone or co-applied with PhTX analogue were studied by using two-electrode voltage-clamp. α3β4 nAChRs were most sensitive to PhTX-343 (IC50=12 nM at −80 mV) with α4β4, α4β2, α3β2, α7 and α1β1γδ being 5, 26, 114, 422 and 992 times less sensitive. In contrast α1β1γδ was most sensitive to PhTX-12 along with α3β4 (IC50values of 100 nM) with α4β4, α4β2, α3β2 and α7 being 3, 3, 26 and 49 times less sensitive. PhTX-343 inhibition was strongly voltage-dependent for all subunit combinations except α7, whereas this was not the case for PhTX-12 for which weak voltage dependence was observed. We conclude that PhTX-343 mainly acts as an open-channel blocker of nAChRs with strong subtype selectivity.

Citation

Kachel, H. S., Patel, R. N., Franzyk, H., & Mellor, I. R. (2016). Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition. Scientific Reports, 6, https://doi.org/10.1038/srep38116

• Journal Article Type: Article
• Acceptance Date: Nov 3, 2016
• Publication Date: Nov 30, 2016
• Deposit Date: Jan 25, 2017
• Publicly Available Date: Jan 25, 2017
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 6
• DOI: https://doi.org/10.1038/srep38116
• Public URL: https://nottingham-repository.worktribe.com/output/826400
• Publisher URL: http://www.nature.com/articles/srep38116
• Contract Date: Jan 25, 2017