Salicylate, an aspirin metabolite, specifically inhibits the current mediated by glycine receptors containing alpha1-subunits.

BACKGROUND AND PURPOSE Aspirin or its metabolite sodium salicylate is widely prescribed and has many side effects. Previous studies suggest that targeting neuronal receptors/ion channels is one of the pathways by which salicylate causes side effects in the nervous system. The present study aimed to investigate the functional action of salicylate on glycine receptors at a molecular level. EXPERIMENTAL APPROACH Whole-cell patch-clamp and site-directed mutagenesis were deployed to examine the effects of salicylate on the currents mediated by native glycine receptors in cultured neurones of rat inferior colliculus and by glycine receptors expressed in HEK293T cells. KEY RESULTS Salicylate effectively inhibited the maximal current mediated by native glycine receptors without altering the EC(50) and the Hill coefficient, demonstrating a non-competitive action of salicylate. Only when applied simultaneously with glycine and extracellularly, could salicylate produce this antagonism. In HEK293T cells transfected with either alpha1-, alpha2-, alpha3-, alpha1beta-, alpha2beta- or alpha3beta-glycine receptors, salicylate only inhibited the current mediated by those receptors that contained the alpha1-subunit. A single site mutation of I240V in the alpha1-subunit abolished inhibition by salicylate. CONCLUSIONS AND IMPLICATIONS Salicylate is a non-competitive antagonist specifically on glycine receptors containing alpha1-subunits. This action critically involves the isoleucine-240 in the first transmembrane segment of the alpha1-subunit. Our findings may increase our understanding of the receptors involved in the side effects of salicylate on the central nervous system, such as seizures and tinnitus.