School of Systems Biology, George Mason University, Manassas, VA 20110, USA.
Department of Cell and Molecular Biology, University of Hawai'i at Manoa, Honolulu, HI 96813, USA.
Trends Pharmacol Sci. 2018 Apr;39(4):354-366. doi: 10.1016/j.tips.2018.01.002. Epub 2018 Feb 7.
The α7 nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel (LGIC) that plays an important role in cellular calcium signaling and contributes to several neurological diseases. Agonist binding to the α7 nAChR induces fast channel activation followed by inactivation and prolonged desensitization while triggering long-lasting calcium signaling. These activities foster neurotransmitter release, synaptic plasticity, and somatodendritic regulation in the brain. We discuss here the ability of α7 nAChRs to operate in ionotropic (α7) and metabotropic (α7) modes, leading to calcium-induced calcium release (CICR) and G protein-associated inositol trisphosphate (IP)-induced calcium release (IICR), respectively. Metabotropic activity extends the spatial and temporal aspects of calcium signaling by the α7 channel beyond its ionotropic limits, persisting into the desensitized state. Delineation of the ionotropic and metabotropic properties of the α7 nAChR will provide definitive indicators of moment-to-moment receptor functional status that will, in turn, spearhead new drug development.
α7 型烟碱型乙酰胆碱受体 (nAChR) 是一种配体门控离子通道 (LGIC)，在细胞钙信号转导中发挥重要作用，并与多种神经退行性疾病有关。激动剂与 α7 nAChR 结合会诱导快速通道激活，随后失活和持续脱敏，同时触发持久的钙信号转导。这些活动促进了大脑中的神经递质释放、突触可塑性和树突体调节。在这里，我们讨论了 α7 nAChR 以离子型 (α7) 和代谢型 (α7) 模式发挥作用的能力，分别导致钙诱导钙释放 (CICR) 和 G 蛋白偶联三磷酸肌醇 (IP) 诱导钙释放 (IICR)。代谢型活性通过 α7 通道将钙信号的时空方面扩展到其离子型限制之外，在脱敏状态下持续存在。对 α7 nAChR 的离子型和代谢型特性的描述将为受体功能状态提供明确的即时指标，这反过来又将为新药开发提供指导。
