Vol. 58, Issue 4, 763-770, October 2000

Glycine Receptor  Subunits Play a Critical Role in Potentiation of Glycine Responses by ICS-205,930

Stephane Supplisson and Dominique Chesnoy-Marchais

Laboratoire de Neurobiologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR-8544, Ecole Normale Supérieure, Paris, France

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 1 or 2 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 1 homomeric GlyRs and inhibiting the responses of 2 homomeric GlyRs. GlyRs  subunits markedly influenced the modulations induced by ICS-205,930. In oocytes expressing 1/ or 2/ 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  subunits reduce by 2 orders of magnitude the concentration range potentiating 1-containing GlyRs and are required for potentiation of 2-containing GlyRs. These results reveal a new high-affinity potentiating site on GlyRs, to which  subunits participate. The difference in ICS sensitivity between 1 and 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.