Salicylate, an aspirin metabolite, specifically inhibits the current mediated by glycine receptors containing 1subunits

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 EC50 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 a1-, a2-, a3-, a1b-, a2bor a3b-glycine receptors, salicylate only inhibited the current mediated by those receptors that contained the a1-subunit. A single site mutation of I240V in the a1-subunit abolished inhibition by salicylate. Conclusions and implications: Salicylate is a non-competitive antagonist specifically on glycine receptors containing a1-subunits. This action critically involves the isoleucine-240 in the first transmembrane segment of the a1-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. British Journal of Pharmacology (2009) 157, 1514–1522; doi:10.1111/j.1476-5381.2009.00321.x; published online 7 July 2009