The Journal of Neuroscience, June 30, 2004, 24(26):5881-5891; doi:10.1523/JNEUROSCI.1037-04.2004
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Cellular/Molecular
The
2 Subunit of GABAA Receptors Is a Substrate for Palmitoylation by GODZ
Cheryl A. Keller,1
Xu Yuan,1
Patrizia Panzanelli,2
Michelle L. Martin,1
Melissa Alldred,1
Marco Sassoè-Pognetto,2 and
Bernhard Lüscher1
1Departments of Biology and Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, 2Department of Anatomy, Pharmacology and Forensic Medicine, and 3Rita Levi Montalcini Center for Brain Repair, University of Turin, I-10126 Turin, Italy
The neurotransmitter GABA activates heteropentameric GABAA receptors, which are composed mostly of
,
, and
2 subunits. Regulated membrane trafficking and subcellular targeting of GABAA receptors is important for determining the efficacy of GABAergic inhibitory function. Of special interest is the
2 subunit, which is mostly dispensable for assembly and membrane insertion of functional receptors but essential for accumulation of GABAA receptors at synapses. In a search for novel receptor trafficking proteins, we have used the SOS-recruitment system and isolated a Golgi-specific DHHC zinc finger protein (GODZ) as a novel
2 subunit-interacting protein. GODZ is a member of the superfamily of DHHC cysteine-rich domain (DHHC-CRD) polytopic membrane proteins shown recently in yeast to represent palmitoyltransferases. GODZ mRNA is found in many tissues; however, in brain the protein is detected in neurons only and highly concentrated and asymmetrically distributed in the Golgi complex. GODZ interacts with a cysteine-rich 14-amino acid domain conserved specifically in the large cytoplasmic loop of
1-3 subunits but not in other GABAA receptor subunits. Coexpression of GODZ and GABAA receptors in heterologous cells results in palmitoylation of the
2 subunit in a cytoplasmic loop domain-dependent manner. Neuronal GABAA receptors are similarly palmitoylated. Thus, GODZ-mediated palmitoylation represents a novel posttranslational modification that is selective for
subunit-containing GABAA receptor subtypes, a mechanism that is likely to be important for regulated trafficking of these receptors in the secretory pathway.
Key words: PAT; trafficking; exocytosis; palmitoyltransferase; SERZ-
; GABA
Received March 21, 2004;
revised April 26, 2004;
accepted May 17, 2004.