Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition

Abstract

The 5-hydroxytryptamine type-3 receptor antagonist tropisetron is in clinical use as an anti-emetic drug. This compound also exerts both potentiating and inhibitory effects on the glycine receptor chloride channel. The inhibitory effects occur at micromolar concentrations, whereas the potentiating effects are shown here to occur at femtomolar concentrations at the homomeric alpha1 receptor. Potentiation occurred only when tropisetron was applied in the presence of glycine. We also sought to identify molecular determinants of tropisetron inhibition at the alpha1 glycine receptor by serially mutating residues located in or near known ligand-binding sites. We discovered that conservative mutati..