Role of the PLC-related, catalytically inactive protein p130 in GABA(A) receptor function.
The protein p130 was isolated from rat brain as an inositol 1,4,5-trisphosphate-binding protein with a domain organization similar to that of phospholipase C-delta1 but lacking PLC activity. We show that p130 plays an important role in signaling by the type A receptor for gamma-aminobutyric acid (GABA). Yeast twohybrid screening identified GABARAP (GABA(A) receptor-associated protein), which is proposed to contribute to the sorting, targeting or clustering of GABA(A) receptors, as a protein that interacts with p130. Furthermore, p130 competitively inhibited the binding of the gamma2 subunit of the GABA(A) receptor to GABARAP in vitro. Electrophysiological analysis revealed that the modulation of GABA-induced Cl- current by Zn2+ or diazepam, both of which act at GABA(A) receptors containing gamma subunits, is impaired in hippocampal neurons of p130 knockout mice. Moreover, behavioral analysis revealed that motor coordination was impaired and the intraperitoneal injection of diazepam induced markedly reduced sedative and antianxiety effects in the mutant mice. These results indicate that p130 is essential for the function of GABA(A) receptors, especially in response to the agents acting on a gamma2 subunit.
Kanematsu
Takashi
T
Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan.
Jang
Il-Sung
IS
Yamaguchi
Taku
T
Nagahama
Hiroyasu
H
Yoshimura
Kenji
K
Hidaka
Kiyoshi
K
Matsuda
Miho
M
Takeuchi
Hiroshi
H
Misumi
Yoshio
Y
Nakayama
Keiko
K
Yamamoto
Tsuneyuki
T
Akaike
Norio
N
Hirata
Masato
M
Nakayama
Kei-Ichi
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D001667:Binding, Competitive; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006993:Hypnotics and Sedatives / Q000494:pharmacology / Q000627:therapeutic use; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology; D007527:Isoenzymes / Q000737:chemistry; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054803:Phospholipase C delta; D021122:Protein Subunits; D021381:Protein Transport; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D010738:Type C Phospholipases / Q000737:chemistry / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D014151:Anti-Anxiety Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D018118:Chloride Channels; D002712:Chlorides; C116741:GABARAP protein, human; D006993:Hypnotics and Sedatives; D007527:Isoenzymes; D046911:Macromolecular Substances; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C430714:Plcl1 protein, rat; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011993:Recombinant Fusion Proteins; D005680:gamma-Aminobutyric Acid; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; C518024:PLCD1 protein, human; D054803:Phospholipase C delta; C518025:Plcd1 protein, mouse; C518026:Plcd1 protein, rat; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D003975:Diazepam