Abstract

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 μM, 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 α1 or α2 subunits, and micromolar concentrations (1–20 μM) acted differentially on the two types of homomeric receptors, potentiating the responses to glycine (10–20 μM) of α1 homomeric GlyRs and inhibiting the responses of α2 homomeric GlyRs. GlyRs β subunits markedly influenced the modulations induced by ICS-205,930. In oocytes expressing α1/β or α2/β heteromeric GlyRs, low concentrations of ICS-205,930 (20 nM–1 μM) induced a potentiation of glycine responses that was counteracted by an inhibitory effect at higher concentrations. Thus, GlyRs β subunits reduce by 2 orders of magnitude the concentration range potentiating α1-containing GlyRs and are required for potentiation of α2-containing GlyRs. These results reveal a new high-affinity potentiating site on GlyRs, to which β subunits participate. The difference in ICS sensitivity between α1 and α2 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-HT₃antagonists with GlyRs.