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

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-...

Full description

Bibliographic Details
Main Authors:	Kachel, Hamid S., Patel, Rohit N., Franzyk, Henrik, Mellor, Ian R.
Format:	Article
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	http://eprints.nottingham.ac.uk/40074/ http://eprints.nottingham.ac.uk/40074/ http://eprints.nottingham.ac.uk/40074/ http://eprints.nottingham.ac.uk/40074/1/Kachel_et_al-2016-Scientific_Reports.pdf

id	nottingham-40074
recordtype	eprints
spelling	nottingham-400742017-10-16T06:45:03Z http://eprints.nottingham.ac.uk/40074/ 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. 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. Nature Publishing Group 2016-11-30 Article PeerReviewed application/pdf en cc_by http://eprints.nottingham.ac.uk/40074/1/Kachel_et_al-2016-Scientific_Reports.pdf Kachel, Hamid S. and Patel, Rohit N. and Franzyk, Henrik and Mellor, Ian R. (2016) Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition. Scientific Reports, 6 . p. 38116. ISSN 2045-2322 http://www.nature.com/articles/srep38116 doi:10.1038/srep38116 doi:10.1038/srep38116
repository_type	Digital Repository
institution_category	Local University
institution	University of Nottingham Malaysia Campus
building	Nottingham Research Data Repository
collection	Online Access
language	English
description	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.
format	Article
author	Kachel, Hamid S. Patel, Rohit N. Franzyk, Henrik Mellor, Ian R.
spellingShingle	Kachel, Hamid S. Patel, Rohit N. Franzyk, Henrik Mellor, Ian R. Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition
author_facet	Kachel, Hamid S. Patel, Rohit N. Franzyk, Henrik Mellor, Ian R.
author_sort	Kachel, Hamid S.
title	Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition
title_short	Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition
title_full	Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition
title_fullStr	Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition
title_full_unstemmed	Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition
title_sort	block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition
publisher	Nature Publishing Group
publishDate	2016
url	http://eprints.nottingham.ac.uk/40074/ http://eprints.nottingham.ac.uk/40074/ http://eprints.nottingham.ac.uk/40074/ http://eprints.nottingham.ac.uk/40074/1/Kachel_et_al-2016-Scientific_Reports.pdf
first_indexed	2018-09-06T13:03:50Z
last_indexed	2018-09-06T13:03:50Z
_version_	1610863377444241408

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

Similar Items