TY - JOUR
T1 - α7 Receptor-selective agonists and modes of α7 receptor activation
AU - Papke, Roger L.
AU - Meyer, Edwin
AU - Nutter, Tom
AU - Uteshev, Vladimir V.
N1 - Funding Information:
Studies were supported by Taiho Pharmaceuticals and by NIH grant NS32888-02. V.U. was supported by a fellowship from the Human Frontier Science Program. We thank Jim Boulter and Jon Lindstrom for the rat and human α7 nicotinic acetylcholine receptor clones, respectively, and Steve Heinemann for the other neuronal nicotinic receptor clones. We also thank Clare Stokes, Mike Francis, and Drs. Robert Oswald, Jon Lindstrom and Stephen Baker for helpful discussions. Single-channel simulation and idealization programs were kindly provided by Drs. Tony Auerbach, Feng Qin and Fred Sachs.
PY - 2000/3/30
Y1 - 2000/3/30
N2 - 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.
AB - 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.
KW - 4OH-GTS-21
KW - GTS-21
KW - α7 Receptor-selective agonist
UR - http://www.scopus.com/inward/record.url?scp=0034731873&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(00)00009-1
DO - 10.1016/S0014-2999(00)00009-1
M3 - Article
C2 - 10771012
AN - SCOPUS:0034731873
SN - 0014-2999
VL - 393
SP - 179
EP - 195
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -