Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine.
Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine.
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发表时间：
1999
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通讯作者：
C. Fenster;T. Whitworth;E. B. Sheffield;M. Quick;R. Lester
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作者：
C. Fenster;T. Whitworth;E. B. Sheffield;M. Quick;R. Lester
据推测，长期接触尼古丁引起的神经元烟碱乙酰胆碱受体（nAChR）脱敏会引发 nAChR 数量的上调。为了直接检验这一假设，将表达α4β2受体的卵母细胞在尼古丁中长期培养（24-48小时），并将与完整卵母细胞表面受体的特异性[3H]尼古丁结合所产生的变化与功能性受体脱敏进行比较。四行证据有力地支持了这一假设。 (1) 产生脱敏所需的半最大尼古丁浓度 (9.7 nM) 与诱导上调所需的半最大尼古丁浓度 (9.9 nM) 相同。 (2) 与完整卵母细胞表面 nAChR 半最大结合的 [3H] 尼古丁浓度也相似 (11.1 nM)，如周期性脱敏模型预测的那样。 (3) α3β4 受体的功能脱敏需要高 10 倍的尼古丁浓度，这反映在上调所需浓度的 10 倍变化上。 (4) 未从脱敏中完全恢复的突变型 α4β2 受体（而非野生型通道）在急性（1 小时）使用尼古丁后上调。有趣的是，全细胞膜匀浆中 α4β2 受体半最大结合所需的尼古丁浓度比完整卵母细胞中表面 nAChR 的测量值低 20 倍。这些数据表明，细胞匀浆结合测定可能无法准确反映表面 nAChR 的体内脱敏亲和力，并且可能解释了先前报道的尼古丁诱导 nAChR 脱敏和上调功效的一些差异。
It is hypothesized that desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) induced by chronic exposure to nicotine initiates upregulation of nAChR number. To test this hypothesis directly, oocytes expressing alpha4beta2 receptors were chronically incubated (24-48 hr) in nicotine, and the resulting changes in specific [3H]nicotine binding to surface receptors on intact oocytes were compared with functional receptor desensitization. Four lines of evidence strongly support the hypothesis. (1) The half-maximal nicotine concentration necessary to produce desensitization (9.7 nM) was the same as that needed to induce upregulation (9.9 nM). (2) The concentration of [3H]nicotine for half-maximal binding to surface nAChRs on intact oocytes was also similar (11.1 nM), as predicted from cyclical desensitization models. (3) Functional desensitization of alpha3beta4 receptors required 10-fold higher nicotine concentrations, and this was mirrored by a 10-fold shift in concentrations necessary for upregulation. (4) Mutant alpha4beta2 receptors that do not recover fully from desensitization, but not wild-type channels, were upregulated after acute (1 hr) applications of nicotine. Interestingly, the nicotine concentration required for half-maximal binding of alpha4beta2 receptors in total cell membrane homogenates was 20-fold lower than that measured for surface nAChRs in intact oocytes. These data suggest that cell homogenate binding assays may not accurately reflect the in vivo desensitization affinity of surface nAChRs and may account for some of the previously reported differences in the efficacy of nicotine for inducing nAChR desensitization and upregulation.