A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore

Abstract

Picrotoxin, an antagonist of structurally-rated GABAA receptors (GABAARs) and glycine receptors (GlyRs), is an equimolar mixture of picrotoxinin (PTXININ) and picrotin (PTN). These compounds share a common structure except that PTN contains a slightly larger dimethylmethanol in place of the PTXININ isopropenyl group. Although the homomeric α1 GlyR is equally sensitive to both compounds, we show here that homomeric α2 and α3 GlyRs, like most GABAARs, are selectively inhibited by PTXININ. As conservative mutations to pore-lining 6′ threonines equally affect the sensitivity of the α1 GlyR to both compounds, we conclude that PTXININ and PTN bind to 6′ threonines by hydrogen bonding with exocycli..