Novel potent AMPA analogues differentially affect desensitisation of AMPA receptors in cultured hippocampal neurons

The agonist actions of two AMPA receptor analogues, (RS)-2-amino-3-(3-carbo xy-5-methyl-4-isoxazolyl) propionic acid (ACPA) and (RS)-2-amino-3-(3-hydro xy-5-trifluoromethyl-4-isoxazolyl)propionic acid (Tri-F-AMPA) have been stu died on cultured rat hippocampal neurons. Whole-cell recordings with semi-r apid application of the agonists were used to study steady-state (plateau) responses. ACPA was the most potent agonist(EC50, 1.2 mu M), followed by AM PA (4.3 mu M) and Tri-F-AMPA (4.6 mu M), corresponding to a potency ratio o f 4:1:1. Hill coefficients were close to 1 for AMPA and ACPA and close to 2 for Tri-F-AMPA, respectively. Plateau responses to maximal concentrations of the three agonists varied more than 2-fold. ACPA responses were 2.1 time s greater and responses to Tri-F-AMPA were 1.6 times greater than responses to AMPA, respectively. Peak responses and desensitization were studied by using a fast piezoelectric device to apply agonists rapidly to outside-out patches. The time constants of desensitization were 8 ms for AMPA, 12 ms fo r Tri-F-AMPA and 17 ms for ACPA. There were no significant differences in t he time-to-peak and 10-90% rise-time of the responses. The results indicate that of the three agonists tested, ACPA is the most potent at AMPA recepto rs expressed in cultured hippocampal neurons and that the maximum response to the agonists is inversely related to the rate of desensitization. (C) 19 99 Elsevier Science B.V. All rights reserved.