Mechanism and impact of allosteric AMPA receptor modulation by the Ampakine (TM) CX546

Glutamate release at central synapses is transduced into a characteristic f ast postsynaptic response by AMPA receptor gating and agonist affinity. The effect of two classes of modulators of AMPA receptor desensitization. the benzothiadiazides (cyclothiazide and IDRA 21) and the benzoylpiperidines (C X516 and CX546), were studied on gating kinetics of recombinant, native AMP A receptors and on synaptic currents. CX546 reduced the degree of desensiti zation more potently than CX516 or IDRA 21, but not as efficiently as cyclo thiazide. In presence of CX516/CX546, desensitization of GluR2(fhp) recepto rs was inhibited more than of GluR1(fhp), whereas they had no effect upon r esponse shape or conductance. CX546 increased agonist affinity threefold on nondesensitizing AMPA receptors by slowing agonist unbinding. Analysis of modulatory action suggests that, in contrast to cyclothiazide or IDRA 21, t he Ampakine (TM) CX546 binds specifically to the agonist bound nondesensiti zed receptor. most likely acting by destabilizing the desensitized receptor conformation. All modulators tested showed higher efficiency on native rec eptors as compared to homomeric receptors. At the glutamatergic synapse, ev oked synaptic amplitudes were weakly potentiated, while EPSC decay was slow ed by nearly a factor of three in the presence of CX546 or cyclothiazide. I n the presence of CX546, the current induced by short pulses of glutamate f rom recombinant GluR2 receptors decayed with a time course that was approxi mately twentyfold faster than EPSCs. The unique properties of CX546 may be beneficial for therapeutical use. (C) 2001 Elsevier Science Ltd. All rights reserved.