4.6 Article

Engineering a Light-Regulated GABAA Receptor for Optical Control of Neural Inhibition

期刊

ACS CHEMICAL BIOLOGY
卷 9, 期 7, 页码 1414-1419

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AMER CHEMICAL SOC
DOI: 10.1021/cb500167u

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  1. National Institute of Health [R01 EY018957, P30 EY003176, PN2 EY018241]
  2. University of Massachusetts, Amherst

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Optogenetics has become an emerging technique for neuroscience investigations owing to the great spatiotemporal precision and the target selectivity it provides. Here we extend the optogenetic strategy to GABA(A) receptors (GABA(A)Rs), the major mediators of inhibitory neurotransmission in the brain. We generated a light-regulated GABA(A) receptor (LiGABAR) by conjugating a photoswitchable tethered ligand (PTL) onto a mutant receptor containing the cysteine-substituted alpha 1-subunit. The installed PTL can be advanced to or retracted from the GABA-binding pocket with 500 and 380 rim light, respectively, resulting in photoswitchable receptor antagonism. In hippocampal neurons, this LiGABAR enabled a robust photoregulation of inhibitory postsynaptic currents. Moreover, it allowed reversible photocontrol over neuron excitation in response to presynaptic stimulation. LiGABAR thus provides a powerful means for functional and mechanistic investigations of GABA(A)R-mediated neural inhibition.

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