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The Journal of Neuroscience, December 6, 2006, 26(49):12758-12768; doi:10.1523/JNEUROSCI.4214-06.2006

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Cellular/Molecular
GODZ-Mediated Palmitoylation of GABA_A Receptors Is Required for Normal Assembly and Function of GABAergic Inhibitory Synapses

Cheng Fang,^1,2,3 Lunbin Deng,^1,3 Cheryl A. Keller,^1,2,3 Masaki Fukata,⁵ Yuko Fukata,⁵ Gong Chen,^1,3 and Bernhard Lüscher^1,2,3,4

¹Department of Biology, ²Department of Biochemistry and Molecular Biology, and ³Penn State Neuroscience Institute, Pennsylvania State University, University Park, Pennsylvania 16802, ⁴Department of Psychiatry, Pennsylvania State University, Hershey, Pennsylvania 17033, and ⁵Laboratory of Genomics and Proteomics, National Institute for Longevity Sciences, Aichi 474-8522, Japan

Correspondence should be addressed to Dr. Bernhard Luscher, Department of Biology and Biochemistry and Molecular Biology, Penn State Neuroscience Institute, Pennsylvania State University, 301 Life Sciences Building, University Park, PA 16802. Email: BXL25{at}psu.edu

Golgi-specific DHHC (Asp-His-His-Cys) zinc finger protein (GODZ) is a DHHC family palmitoyl acyltransferase that is implicated in palmitoylation and regulated trafficking of diverse substrates that function either at inhibitory or excitatory synapses. Of particular interest is the 2 subunit of GABA_A receptors, which is required for targeting these receptors to inhibitory synapses. Here, we report that GODZ and, to a lesser extent, its close paralog sertoli cell gene with a zinc finger domain-ß (SERZ-ß) are the main members of the DHHC family of enzymes that are able to palmitoylate the 2 subunit in heterologous cells. Yeast two-hybrid and colocalization assays in human embryonic kidney 293T (HEK293T) cells indicate that GODZ and SERZ-ß show indistinguishable palmitoylation-dependent interaction with the 2 subunit. After coexpression in HEK293T cells, they form homomultimers and heteromultimers, as shown by coimmunoprecipitation and in vivo cross-linking experiments. Analyses in neurons transfected with dominant-negative GODZ (GODZ^C157S) or plasmid-based GODZ-specific RNAi indicate that GODZ is required for normal accumulation of GABA_A receptors at synapses, for normal whole-cell and synaptic GABAergic inhibitory function and, indirectly, for GABAergic innervation. Unexpectedly, GODZ was found to be dispensable for normal postsynaptic AMPA receptor-mediated glutamatergic transmission. We conclude that GODZ-mediated palmitoylation of GABA_A receptors and possibly other substrates contributes selectively to the formation and normal function of GABAergic inhibitory synapses.

Key words: trafficking; synaptogenesis; inhibitory synapses; palmitoylation; DHHC-CRD proteins; GABA_A receptors

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Received May 26, 2006; revised Oct. 25, 2006; accepted Oct. 27, 2006.

Correspondence should be addressed to Dr. Bernhard Luscher, Department of Biology and Biochemistry and Molecular Biology, Penn State Neuroscience Institute, Pennsylvania State University, 301 Life Sciences Building, University Park, PA 16802. Email: BXL25{at}psu.edu

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