Tomita Susumu, Sekiguchi Masayuki, Wada Keiji, Nicoll Roger A, Bredt David S
Department of Physiology, University of California-San Francisco, San Francisco, CA 94143, USA.
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10064-7. doi: 10.1073/pnas.0603128103. Epub 2006 Jun 19.
Glutamate is the major excitatory neurotransmitter in brain, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) mediate the majority of postsynaptic depolarization. AMPAR ion channels display rapid gating, and their deactivation and desensitization determine the timing of synaptic transmission. AMPAR potentiators slow channel deactivation and desensitization, and these compounds represent exciting therapies for mental and neurodegenerative diseases. Previous studies showed that the AMPAR potentiators cyclothiazide and 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide display a preference for flip and flop alternatively spliced versions of glutamate receptor subunits, respectively. Here, we find that the AMPAR auxiliary subunit stargazin changes this pharmacology and makes both spliced forms of glutamate receptor subunit 1 sensitive to both classes of potentiator. Stargazin also enhances the effect of AMPAR potentiators on channel deactivation. This work demonstrates that stargazin controls AMPAR potentiator pharmacology, which has important implications for development of AMPAR potentiators as therapeutic agents.
谷氨酸是大脑中的主要兴奋性神经递质，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体（AMPARs）介导了大部分突触后去极化。AMPAR离子通道表现出快速门控，其失活和脱敏决定了突触传递的时间。AMPAR增强剂可减缓通道失活和脱敏，这些化合物代表了治疗精神疾病和神经退行性疾病的激动人心的疗法。先前的研究表明，AMPAR增强剂环噻嗪和4-[2-(苯磺酰氨基)乙硫基]-2,6-二氟苯氧基乙酰胺分别对谷氨酸受体亚基的翻转和摆动剪接变体表现出偏好。在这里，我们发现AMPAR辅助亚基stargazin改变了这种药理学特性，使谷氨酸受体亚基1的两种剪接形式对这两类增强剂都敏感。Stargazin还增强了AMPAR增强剂对通道失活的作用。这项工作表明stargazin控制着AMPAR增强剂的药理学特性，这对开发作为治疗剂的AMPAR增强剂具有重要意义。
