Biophysics Graduate Group, University of California, Berkeley, California, USA.
Nat Neurosci. 2013 Apr;16(4):507-16. doi: 10.1038/nn.3346. Epub 2013 Mar 3.
G protein-coupled receptors (GPCRs), the largest family of membrane signaling proteins, respond to neurotransmitters, hormones and small environmental molecules. The neuronal function of many GPCRs has been difficult to resolve because of an inability to gate them with subtype specificity, spatial precision, speed and reversibility. To address this, we developed an approach for opto-chemical engineering of native GPCRs. We applied this to the metabotropic glutamate receptors (mGluRs) to generate light-agonized and light-antagonized mGluRs (LimGluRs). The light-agonized LimGluR2, on which we focused, was fast, bistable and supported multiple rounds of on/off switching. Light gated two of the primary neuronal functions of mGluR2: suppression of excitability and inhibition of neurotransmitter release. We found that the light-antagonized tool LimGluR2-block was able to manipulate negative feedback of synaptically released glutamate on transmitter release. We generalized the optical control to two additional family members: mGluR3 and mGluR6. This system worked in rodent brain slices and in zebrafish in vivo, where we found that mGluR2 modulated the threshold for escape behavior. These light-gated mGluRs pave the way for determining the roles of mGluRs in synaptic plasticity, memory and disease.
G 蛋白偶联受体（GPCRs）是最大的膜信号蛋白家族，可响应神经递质、激素和小环境分子。由于无法以亚型特异性、空间精度、速度和可逆性对其进行门控，许多 GPCR 的神经元功能一直难以确定。为了解决这个问题，我们开发了一种对天然 GPCR 进行光电化学工程的方法。我们将其应用于代谢型谷氨酸受体（mGluRs），以产生光激动型和光拮抗型 mGluRs（LimGluRs）。我们重点研究的光激动型 LimGluR2 快速、双稳态且支持多次开/关切换。光门控了 mGluR2 的两种主要神经元功能：抑制兴奋性和抑制神经递质释放。我们发现光拮抗型工具 LimGluR2-block 能够操纵突触释放的谷氨酸对递质释放的负反馈。我们将光学控制推广到另外两个家族成员：mGluR3 和 mGluR6。该系统在啮齿动物脑片和斑马鱼体内均有效，我们发现 mGluR2 调节了逃避行为的阈值。这些光门控的 mGluRs 为确定 mGluRs 在突触可塑性、记忆和疾病中的作用铺平了道路。
