α7 Receptor-selective agonists and modes of α7 receptor activation

The α7-selective agonists 3-(2,4-dimethoxybenzylidene)-anabaseine (GTS-21), also known as DMXB, and 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21) produce a variety of behavioral and cytoprotective effects that may be related to the activation of either large transient currents at high concentrations or small sustained currents at lower agonist concentrations. We are using acutely dissociated hypothalamic neurons, which express a central nervous system (CNS) α7-type receptor, to test a model for the concentration-dependent desensitization of α7-mediated responses. Our results confirm that 4OH-GTS-21 is a potent activator of neuronal α7 nicotinic-acetylcholine receptor. The rapid application of agonist leads to a brief period of maximal receptor-activation followed by desensitization. Rise rates, decay rates, and the degree to which current was desensitized were all concentration-dependent. Following the initial peak response to a 300-μM 4OH-GTS-21 application, current is reduced to baseline values within about 100 ms. Application of 30 μM 4OH-GTS-21 produced both a transient peak current and a sustained current that decayed only slowly after the removal of agonist. In the case of a 300-μM 4OH-GTS-21 application, after agonist was removed, we saw a rebound response up to the level of the 30-μM sustained current. The data, therefore, suggest that a sufficient level of agonist occupation can be retained on the receptor to promote activation for up to several hundred milliseconds. Copyright (C) 2000 Elsevier Science B.V.