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The Journal of Neuroscience, December 15, 2004, 24(50):11429-11438; doi:10.1523/JNEUROSCI.3355-04.2004

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Cellular/Molecular
GABA_A Receptor-Associated Protein Traffics GABA_A Receptors to the Plasma Membrane in Neurons

Tarek A. Leil, Zi-Wei Chen, Chang-Sheng S. Chang, and Richard W. Olsen

Department of Molecular and Medical Pharmacology, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1735

The trafficking of GABA_A receptors is an important component of the pathway that regulates plasticity of inhibitory synapses. The 17 kDa GABA_A receptor-associated protein (GABARAP) has been implicated in the trafficking of GABA_A receptors because of its ability to interact not only with the 2 subunit of the receptor but also with microtubules and the N-ethylmaleimide-sensitive factor (NSF). To elucidate the role of GABARAP in the trafficking of GABA_A receptors, we have constructed a yellow fluorescent protein (YFP) fusion protein of GABARAP and expressed it in neurons using adenovirus, so that its function may be examined. YFP-GABARAP colocalized with 2 subunit-containing GABA_A receptors and NSF to the perinuclear cytoplasm in cultured hippocampal neurons and to the proximal regions of dendrites that are making synaptic contact. Expression of YFP-GABARAP in Cos7 cells and cultured hippocampal neurons was able to increase the level of GABA_A receptors detected at the plasma membrane, even at low levels of YFP-GABARAP expression. This effect is specific to the function of GABARAP on GABA_A receptor trafficking, because point mutations in the 2-binding domain of YFP-GABARAP interfered with the ability of YFP-GABARAP to increase GABA_A receptor surface levels. These mutations also disrupted the colocalization of YFP-GABARAP with the 2 subunit and with NSF in hippocampal neurons. The results of this study show for the first time that GABARAP has a functional effect on the trafficking of GABA_A receptors and provide decisive evidence for the role of GABARAP in transporting GABA_A receptors to the plasma membrane in neurons.

Key words: GABARAP; GABA_A receptor; trafficking; neurons; synapse; Cos7

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Received Aug 16, 2004; revised November 8, 2004; accepted November 8, 2004.

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