Contrasting Actions of Philanthotoxin-343 and Philanthotoxin-(12) on Human Muscle Nicotinic Acetylcholine Receptors

Abstract

Whole-cell recordings and outside-out patch recordings from TE671 cells were made to investigate antagonism of human muscle nicotinic acetylcholine receptors (nAChR) by the philanthotoxins, . When coapplied with acetylcholine (ACh), PhTX-343 caused activation-dependent, noncompetitive inhibition (IC 50 ϭ 17 M at Ϫ100 mV) of wholecell currents that was strongly voltage-dependent. However, preapplication of PhTX-343 unveiled a voltage-independent antagonism that also required receptor activation, which is suggestive of desensitization enhancement.

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

“…As expected PhTX-12 displayed significantly reduced potency at AMPA receptors and slightly reduced potency at NMDA receptors, but unexpectedly exhibited increased potency at muscle-type nAChRs513. However, the latter finding was associated with a change in mode of action whereby the inhibition was weakly voltage-dependent, remaining strong at positive membrane potentials811.…”

“…Apart from its inhibitory action on insect nAChRs and iGluRs, PhTX-433 and its closely related synthetic analogue, PhTX-343 (Fig. 1), also exhibit potent activity at vertebrate ionotropic receptors, and their receptor interactions have been quite extensively characterized for mammalian iGluRs, including the AMPA, kainate and NMDA receptor subtypes3456, as well as for vertebrate muscle-type nAChRs78. These investigations have inferred that philanthotoxins (PhTXs) display some selectivity towards iGluRs over nAChRs.…”

AMPA receptor ligands: Synthetic and pharmacological studies of polyamines and polyamine toxins

“…228 The toxins showed potent (IC 50 ¼ 100-200 nM, À60 mV) voltage-dependent inhibition indicating open channel block. PhTX-343 (21) has also been studied on muscle type nAChR 135,159,160,229 where it also causes open channel block, 229 but only at much higher concentrations (IC 50 ¼ 17 mM), 160,229 although other modes of action have been identified. [229][230][231] However, if amino groups are removed from PhTX-343 (21) the resultant compounds become more potent at muscle type nAChR, 135,136,159 but there is a simultaneous change in the mode of action that is still non-competitive and is characterized by voltage-independent and activation-dependent antagonism.…”

“…[229][230][231] However, if amino groups are removed from PhTX-343 (21) the resultant compounds become more potent at muscle type nAChR, 135,136,159 but there is a simultaneous change in the mode of action that is still non-competitive and is characterized by voltage-independent and activation-dependent antagonism. 229,231 This is interpreted as enhancement of agonist induced nAChR desensitization. As a general rule, more hydrophobic analogues of PhTX-343 (21) adopt this mode of action.…”

Insect natural products and processes: New treatments for human disease

“…Wasp venom also contains other non-kinin, neurotoxins such as philanthotoxin (PhTX), a polyamine amide from the solitary wasp Philanthus triangulum, which is a non-competitive inhibitor of nicotinic acetylcholine and glutamate receptors in the mammalian brain (Brier et al, 2003). This toxin has been used to label and study Ca 2þ -permeable glutamate receptors which are implicated in ischaemic conditions, epilepsy and growth of glioblastomas (Osswald et al, 2007).…”