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

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. ?3?4 nAChRs were most sensitive to PhTX-343 (IC50?=?12?nM at -80?mV) with ?4?4, ?4?2, ?3?2, ?7 and ?1?1?? being 5, 26, 114, 422 and 992 times less sensitive. In contrast ?1?1?? was most sensitive to PhTX-12 along with ?3?4 (IC50 values of 100?nM) with ?4?4, ?4?2, ?3?2 and ?7 being 3, 3, 26 and 49 times less sensitive. PhTX-343 inhibition was strongly voltage-dependent for all subunit combinations except ?7, 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.

SUBMITTER: Kachel HS 

PROVIDER: S-EPMC5128878 | biostudies-other | 2016 Nov

REPOSITORIES: biostudies-other