Pinnatoxins E, F and G target multiple nicotinic receptor subtypes

Area of Science:

• Marine toxicology
• Neuroscience
• Pharmacology

Background:

• Pinnatoxins are highly toxic cyclic imine marine phycotoxins.
• Pinnatoxins E, F, and G antagonize muscle-type nicotinic acetylcholine receptors (nAChRs).
• The specific interactions of these isomers with neuronal nAChRs remain largely uncharacterized.

Purpose of the Study:

• To investigate the binding affinities and modes of pinnatoxins E, F, and G at muscle and neuronal nAChRs.
• To determine the functional effects of these pinnatoxin isomers on neuronal nAChRs.
• To elucidate the molecular interactions underlying pinnatoxin binding to nAChRs.

Main Methods:

• Radioligand binding assays to assess affinity.
• Electrophysiology (Xenopus oocytes) to evaluate functional antagonism.
• Molecular modeling to visualize binding site interactions.

Main Results:

• Pinnatoxins E, F, and G exhibited high affinity for muscle-type nAChRs, followed by α7 and α4β2 neuronal nAChRs.
• Potency order was consistently pinnatoxin F > G > E across all tested nAChR subtypes.
• Pinnatoxins F and G functionally antagonized acetylcholine responses at α7 and α4β2 neuronal receptors.
• Molecular modeling indicated extensive hydrogen bonding at muscle and α7 nAChR binding sites, with fewer interactions at α4β2 nAChRs.

Conclusions:

• Pinnatoxins E, F, and G bind to and antagonize neuronal nicotinic acetylcholine receptors.
• These interactions with neuronal nAChRs represent a novel mechanism contributing to pinnatoxin toxicity.
• The differential binding affinities and interactions provide insights into the structure-activity relationships of pinnatoxin isomers.