Abstract
Alterations in the polyamine and amino acid (tyrosine) moieties of philanthotoxin-343 (PhTX-343) were investigated for their effects on the antagonism of nicotinic acetylcholine receptors (nAChRs) isolated from the locust (Schistocerca gregaria) mushroom body. Through whole-cell patch-clamp recordings, the philanthotoxin analogues in this study were shown to cause inhibition of the inward current when co-applied with acetylcholine (ACh). PhTX-343 (IC50 = 0.80 μM at −75 mV) antagonised locust nAChRs in a use-dependent manner, suggesting that it acts as an open-channel blocker. The analogue in which both the secondary amine functionalities were replaced with methylene groups (i.e., PhTX-12) was ~6-fold more potent (IC50 (half-maximal inhibitory concentration) = 0.13 μM at −75 mV) than PhTX-343. The analogue containing cyclohexylalanine as a substitute for the tyrosine moiety of PhTX-343 (i.e., Cha-PhTX-343) was also more potent (IC50 = 0.44 μM at −75 mV). A combination of both alterations to PhTX-343 generated the most potent analogue, i.e., Cha-PhTX-12 (IC50 = 1.71 nM at −75 mV). Modulation by PhTX-343 and Cha-PhTX-343 fell into two distinct groups, indicating the presence of two pharmacologically distinct nAChR groups in the locust mushroom body. In the first group, all concentrations of PhTX-343 and Cha-PhTX-343 inhibited responses to ACh. In the second group, application of PhTX-343 or Cha-PhTX-343 at concentrations ≤100 nM caused potentiation, while concentrations ≥ 1 μM inhibited responses to ACh. Cha-PhTX-12 may have potential to be developed into insecticidal compounds with a novel mode of action.
Highlights
Venoms from many predatory wasps and spiders contain polyamine toxins that have been used as pharmacological tools in the study of ionotropic receptors, but their value has been limited due to a lack of selectivity [1]
PhTX-343 (IC50 = 0.80 μM at −75 mV) antagonised locust nicotinic acetylcholine receptors (nAChRs) in a use-dependent manner, suggesting that it acts as an open-channel blocker
Modulation by PhTX-343 and ChaPhTX-343 fell into two distinct groups, indicating the presence of two pharmacologically distinct nAChR groups in the locust mushroom body
Summary
Venoms from many predatory wasps and spiders contain polyamine toxins that have been used as pharmacological tools in the study of ionotropic receptors, but their value has been limited due to a lack of selectivity [1]. Among these polyamine toxins, philanthotoxins (PhTXs) are of particular interest. The modular structure of PhTX-433 (Figure 1a) facilitates the development of novel synthetic analogues that can be made specific against particular ionotropic receptors [2]. PhTX-433 and its synthetic analogues are non-competitive antagonists of ionotropic glutamate receptors of vertebrate nervous systems and insect muscles, as well as of nicotinic acetylcholine receptors (nAChR), expressed by the cells of a variety of organisms, including human muscles [3,4], the mammalian central nervous system (CNS) [5,6,7], and the insect CNS [8].
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