Glycine receptor β subunits play a critical role in potentiation of glycine responses by ICS-205,930

The sensitivity of various types of recombinant glycine receptors (GlyRs) to ICS-205,930 was studied by fast perfusion in Xenopus laevis oocytes. This compound has previously been shown to potentiate glycine responses in rat spinal neurons between 10 nM and 1 mu M, independently of its 5-HT3 antagonist properties. In contrast, submicromolar concentrations of ICS-205,930 failed to affect responses of homomeric GlyRs formed from human alpha 1 or alpha 2 subunits, and micromolar concentrations (1-20 mu M) acted differentially on the two types of homomeric receptors, potentiating the responses to glycine (10-20 mu M) of alpha 1 homomeric GlyRs and inhibiting the responses of alpha 2 homomeric GlyRs. GlyRs beta subunits markedly influenced the modulations induced by ICS-205,930. In oocytes expressing alpha 1/beta or alpha 2/beta heteromeric GlyRs, low concentrations of ICS-205,930 (20 nM-1 mu M) induced a potentiation of glycine responses that was counteracted by an inhibitory effect at higher concentrations. Thus, GlyRs beta subunits reduce by 2 orders of magnitude the concentration range potentiating alpha 1-containing GlyRs and are required for potentiation of alpha 2-containing GlyRs. These results reveal a new high-affinity potentiating site on GlyRs, to which beta subunits participate. The difference in ICS sensitivity between alpha 1 and alpha 2 GlyRs cannot be explained by their difference in TM2 segment and extracellular domains partly conserved between glycine and 5-HT3 receptors are probably involved in the interaction of some 5-HT3 antagonists with GlyRs.