GODZ-mediated palmitoylation of GABAA receptors is required for normal assembly and function of GABAergic inhibitory synapses

被引:137
作者
Fang, Cheng
Deng, Lunbin
Keller, Cheryl A.
Fukata, Masaki
Fukata, Yuko
Chen, Gong
Luscher, Bernhard
机构
[1] Penn State Univ, Dept Biol, Penn State Neurosci Inst, University Pk, PA 16802 USA
[2] Penn State Univ, Dept Biochem & Mol Biol, Penn State Neurosci Inst, University Pk, PA 16802 USA
[3] Penn State Univ, Dept Psychiat, Hershey, PA 17033 USA
[4] Natl Inst Longev Sci, Lab Genom & Proteom, Aichi 4748522, Japan
关键词
trafficking; synaptogenesis; inhibitory synapses; palmitoylation; DHHC-CRD proteins; GABA(A) receptors;
D O I
10.1523/JNEUROSCI.4214-06.2006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 gamma 2 subunit of GABAA 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-beta (SERZ-beta) are the main members of the DHHC family of enzymes that are able to palmitoylate the gamma 2 subunit in heterologous cells. Yeast two-hybrid and colocalization assays in human embryonic kidney 293T (HEK293T) cells indicate that GODZ and SERZ-beta show indistinguishable palmitoylation-dependent interaction with the gamma 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 GABAA receptors and possibly other substrates contributes selectively to the formation and normal function of GABAergic inhibitory synapses.
引用
收藏
页码:12758 / 12768
页数:11
相关论文
共 36 条
[1]   Distinct γ2 subunit domains mediate clustering and synaptic function of postsynaptic GABAA receptors and gephyrin [J].
Alldred, MJ ;
Mulder-Rosi, J ;
Lingenfelter, SE ;
Chen, G ;
Lüscher, B .
JOURNAL OF NEUROSCIENCE, 2005, 25 (03) :594-603
[2]   Postsynaptic clustering of γ-aminobutyric acid type A receptors by the γ3 subunit in vivo [J].
Baer, K ;
Essrich, C ;
Benson, JA ;
Benke, D ;
Bluethmann, H ;
Fritschy, JM ;
Lüscher, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (22) :12860-12865
[3]   GABAA receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1 [J].
Bedford, FK ;
Kittler, JT ;
Muller, E ;
Thomas, P ;
Uren, JM ;
Merlo, D ;
Wisden, W ;
Triller, A ;
Smart, TG ;
Moss, SJ .
NATURE NEUROSCIENCE, 2001, 4 (09) :908-916
[4]   The on-off story of protein palmitoylation [J].
Bijlmakers, MJ ;
Marsh, M .
TRENDS IN CELL BIOLOGY, 2003, 13 (01) :32-42
[5]   Synaptic GABAA receptors are directly recruited from their extrasynaptic counterparts [J].
Bogdanov, Yury ;
Michels, Guido ;
Armstrong-Gold, Cecilia ;
Haydon, Philip G. ;
Lindstrom, Jon ;
Pangalos, Menelas ;
Moss, Stephen J. .
EMBO JOURNAL, 2006, 25 (18) :4381-4389
[6]   Intact sorting, targeting, and clustering of γ-aminobutyric acid A receptor subtypes in hippocampal neurons in vitro [J].
Brünig, I ;
Scotti, E ;
Sidler, C ;
Fritschy, JM .
JOURNAL OF COMPARATIVE NEUROLOGY, 2002, 443 (01) :43-55
[7]   Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing, γ-aminobutyric acid type A receptors [J].
Caraiscos, VB ;
Elliott, EM ;
You-Ten, KE ;
Cheng, VY ;
Belelli, D ;
Newell, JG ;
Jackson, MF ;
Lambert, JJ ;
Rosahl, TW ;
Wafford, KA ;
MacDonald, JF ;
Orser, BA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (10) :3662-3667
[8]   Identification of a novel gene product, Sertoli cell gene with a zinc finger domain, that is important for FSH activation of testicular Sertoli cells [J].
Chaudhary, J ;
Skinner, MK .
ENDOCRINOLOGY, 2002, 143 (02) :426-435
[9]   Excitatory actions of GABA in developing rat hypothalamic neurones [J].
Chen, G ;
Trombley, PQ ;
vandenPol, AN .
JOURNAL OF PHYSIOLOGY-LONDON, 1996, 494 (02) :451-464
[10]   Clustered and non-clustered GABAA receptors in cultured hippocampal neurons [J].
Christie, SB ;
Li, RW ;
Miralles, CP ;
Yang, BY ;
De Blas, AL .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2006, 31 (01) :1-14