The gamma2 subunit of GABA(A) receptors is a substrate for palmitoylation by GODZ

The neurotransmitter GABA activates heteropentameric GABAAreceptors, which are composed mostly of α, β, and γ2 subunits. Regulated membrane trafficking and subcellular targeting of GABAAreceptors is important for determining the efficacy of GABAergic inhibitory function. Of special interest is the γ2 subunit, which is mostly dispensable for assembly and membrane insertion of functional receptors but essential for accumulation of GABAAreceptors 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 γ2 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 γ1-3 subunits but not in other GABAAreceptor subunits. Coexpression of GODZ and GABAAreceptors in heterologous cells results in palmitoylation of the γ2 subunit in a cytoplasmic loop domain-dependent manner. Neuronal GABAAreceptors are similarly palmitoylated. Thus, GODZ-mediated palmitoylation represents a novel posttranslational modification that is selective forγ subunit-containing GABAAreceptor subtypes, a mechanism that is likely to be important for regulated trafficking of these receptors in the secretory pathway.