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8.C.1 The Picrotoxin (Picrotoxin) Family

Picrotoxin (PTX), also known as cocculin, is a poisonous crystalline plant alkaloid, first isolated by Boullay in 1812.  It is found primarily in Cocculus indicus and Anamirta cocculus, and it acts as a non-competitve antagonist of GABA A receptors.  As GABA itself is an inhibitory neurotransmitter, infusion of picrotoxin has a stimulative effect.  Its chemical formula (C30H34O13) includes two substances, picrotoxinin (C16H16O6) and picrotin (C15H18O7).  It also binds to and induces conformational changes in the glycine receptor M2-M3 loop (Hawthorne and Lynch 2005).

Picrotoxin (PTX) is a non-competitive antagonist of many ligand-gated ion channels, with a site of action believed to be within the ion-conducting pore.  In the GABAA receptor, a threonine residue in the second transmembrane domain (M2) is of particular importance for the binding of, and ultimate inhibition by, PTX.  An interaction between PTX and three adjacent uncharged polar amino acids at this position of the pore are crucial for PTX-mediated inhibition (Erkkila et al., 2008). PTX-mediated antagonism of alpha3beta4 and alpha7 acetylcholine receptors has been described (Erkkila et al. 2004).

References associated with 8.C.1 family:

Erkkila, B.E., A.V. Sedelnikova, and D.S. Weiss. (2008). Stoichiometric pore mutations of the GABAAR reveal a pattern of hydrogen bonding with picrotoxin. Biophys. J. 94: 4299-4306. 18310243
Erkkila, B.E., D.S. Weiss, and V.E. Wotring. (2004). Picrotoxin-mediated antagonism of alpha3beta4 and alpha7 acetylcholine receptors. Neuroreport 15: 1969-1973. 15305147
Hawthorne, R. and J.W. Lynch. (2005). A picrotoxin-specific conformational change in the glycine receptor M2-M3 loop. J. Biol. Chem. 280: 35836-35843. 16109711