Nagarajan N, Quast C, Boxall A R, Shahid M, Rosenmund C
Department of Membrane Biophysics, Max-Planck-Institute for Biophysical Chemistry, D-37070, Goettingen, Germany.
Neuropharmacology. 2001 Nov;41(6):650-63. doi: 10.1016/s0028-3908(01)00133-2.
Glutamate release at central synapses is transduced into a characteristic fast 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 (CX516 and CX546), were studied on gating kinetics of recombinant, native AMPA receptors and on synaptic currents. CX546 reduced the degree of desensitization more potently than CX516 or IDRA 21, but not as efficiently as cyclothiazide. In presence of CX516/CX546, desensitization of GluR2(flip) receptors was inhibited more than of GluR1(flip), whereas they had no effect upon response 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, the Ampakine CX546 binds specifically to the agonist bound nondesensitized receptor, most likely acting by destabilizing the desensitized receptor conformation. All modulators tested showed higher efficiency on native receptors as compared to homomeric receptors. At the glutamatergic synapse, evoked synaptic amplitudes were weakly potentiated, while EPSC decay was slowed by nearly a factor of three in the presence of CX546 or cyclothiazide. In the presence of CX546, the current induced by short pulses of glutamate from recombinant GluR2 receptors decayed with a time course that was approximately twentyfold faster than EPSCs. The unique properties of CX546 may be beneficial for therapeutical use.
中枢突触处谷氨酸的释放通过AMPA受体门控和激动剂亲和力转化为特征性的快速突触后反应。研究了两类AMPA受体脱敏调节剂，即苯并噻二嗪类（环噻嗪和IDRA 21）和苯甲酰哌啶类（CX516和CX546）对重组天然AMPA受体门控动力学和突触电流的影响。CX546比CX516或IDRA 21更有效地降低脱敏程度，但不如环噻嗪有效。在存在CX516/CX546的情况下，GluR2（翻转）受体的脱敏比GluR1（翻转）受体受到的抑制更多，而它们对反应形状或电导没有影响。CX546通过减缓激动剂解离，使非脱敏AMPA受体上的激动剂亲和力增加了三倍。调节作用分析表明，与环噻嗪或IDRA 21不同，AMPA激动剂CX546特异性结合激动剂结合的非脱敏受体，最有可能通过破坏脱敏受体构象起作用。与同聚体受体相比，所有测试的调节剂对天然受体显示出更高的效率。在谷氨酸能突触处，诱发的突触幅度被微弱增强，而在存在CX546或环噻嗪的情况下，EPSC衰减减慢了近三倍。在存在CX546的情况下，重组GluR2受体的谷氨酸短脉冲诱导的电流衰减的时间进程比EPSC快约二十倍。CX546的独特性质可能有利于治疗应用。
