Gymnopilins, a product of a hallucinogenic mushroom, inhibit the nicotinic acetylcholine receptor

• Gymnopilins partially reduce the amplitude of intracellular Ca2+ rises evoked by ACh in PC12 cells.
• Gymnopilins abolish intracellular Ca2+ rises evoked by DMPP and nicotine, and that by ACh in the presence of atropine.
• Gymnopilins inhibit DMPP-induced currents, but do not affect voltage-gated Ca2+ channel currents.
• Gymnopilins seem to directly inhibit nicotinic ACh receptors.

Gymnopilins are substances produced in fruiting bodies of the hallucinogenic mushroom, Gymnopilus junonius. Although, only a few biological effects of gymnopilins on animal tissues have been reported, it is believed that gymnopilins are a key factor of the G. junonius poisoning. In the present study, we found that gymnopilins inhibited ACh-evoked responses in neuronal cell line, PC12 cell, and determine the underlying mechanism. Gymnopilins were purified from wild fruiting bodies of G. junonius collected in Japan. Ca2+-imaging revealed that gymnopilins reduced the amplitude of ACh-evoked [Ca2+]i rises by about 50% and abolished the ACh responses remaining in the presence of atropine. Gymnopilins greatly reduced the amplitude of [Ca2+]i rises evoked by nicotinic ACh receptor agonists, 1,1-Dimethyl-4-phenylpiperazinium iodide (DMPP) and nicotine. In the whole-cell voltage clamp recording, gymnopilins inhibited the DMPP-evoked currents, but did not affect the voltage-gated Ca2+ channel currents. These results indicate that gymnopilins directly act on nicotinic ACh receptors and inhibit their activity. This biological action of gymnopilins may be one of the causes of the G. junonius poisoning.