Palmitoylation regulates the clustering and cell surface stability of GABAA receptors

GABA(A) receptors are the major mediators of fast synaptic inhibition in the brain. These receptors are ionotropic, hetero-pentameric, ligand-gated ion channels, which are predominantly composed of alpha, beta, and gamma2 subunits. Here, we reveal that the gamma2 subunit of neuronal and recombinant GABA(A) receptors is palmitoylated. We further establish that palymitoylation of the gamma2 subunit occurs on multiple cysteine residues within the major intracellular domain of this receptor subunit. In cultured hippocampal neurons, inhibitors of protein palymitoylation reduced the synaptic clustering of GABA(A) receptors and steady-state cell surface receptor number. These effects are likely to be mediated by direct palmitoylation of the gamma2 subunit, as mutation of palmitoylation sites within this protein reduces GABA(A) receptor clustering. Taken together, these results suggest that palmitoylation of GABA(A) receptors plays an essential role in regulating the clustering of these receptors at synaptic sites. (C) 2004 Elsevier Inc. All rights reserved.