Studies of the antagonist actions of (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazoly]propionic acid (ATPO) on non-NMDA receptors in cultured rat neurones

1 Whole-cell patch-clamp recordings from single cultured cortical neurones have been used to study the action of (RS)-2-amino-3-[5-tert-butyl-3-(phosp honomethoxy)-4-isoxazolyl]propionic acid (ATPO), which has previously been proposed to be a potent selective antagonist of 2-amino-3-(3-hydroxy-5-meth yl-4-isoxazolyl)propionic acid (AMPA) receptors. 2 ATPO competitively reduced peak responses evoked by semi-rapid applicatio ns of AMPA (K-i=16 mu M) but had variable effects on plateau responses, whi ch were on average unchanged. Following blockade of AMPA receptor desensiti zation by cyclothiazide (CTZ, 100 mu M), the plateau responses were reduced by ATPO to a similar extent as the peak responses, indicating that ATPO re duces desensitization of AMPA receptors. 3 Semi-rapid application of kainic acid (KA) and the KA receptor-selective agonist, (2S,4R)-4-methylglutamic acid (MeGlu) evoked non-desensitizing res ponses which were competitively antagonized by ATPO (Ki values: 27 and 23 m u M, respectively). 4 Responses to MeGlu were unaffected by CTZ (100 mu M), but potentiated 3 f old following blockade of KA receptor desensitization by concanavalin A (Co n A, 300 mu g ml(-1)). Responses of spinal cord neurones to MeGlu were bloc ked by ATPO to a similar extent before and after blockade of KA receptor de sensitization by Con A. 5 Although selectively potentiated by Con A, plateau responses to MeGlu wer e reduced by 69.6% by the AMPA selective antagonist, GYKI 53655 (10 mu M). The remaining component was further reduced by ATPO with a K-i of 36 mu M, which was not significantly different from that in the absence of GYKI 5365 5, but was greater than that on responses to AMPA. 6 It is concluded that ATPO is a moderate-potency competitive inhibitor of naturally expressed non-NMDA receptors.