PMID- 23077067
OWN - NLM
STAT- MEDLINE
DCOM- 20130102
LR  - 20211021
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 32
IP  - 42
DP  - 2012 Oct 17
TI  - A comprehensive small interfering RNA screen identifies signaling pathways 
      required for gephyrin clustering.
PG  - 14821-34
LID - 10.1523/JNEUROSCI.1261-12.2012 [doi]
AB  - The postsynaptic scaffold protein gephyrin is clustered at inhibitory synapses 
      and serves for the stabilization of GABA(A) receptors. Here, a comprehensive 
      kinome-wide siRNA screen in a human HeLa cell-based model for gephyrin clustering 
      was used to identify candidate protein kinases implicated in the stabilization of 
      gephyrin clusters. As a result, 12 hits were identified including FGFR1 (FGF 
      receptor 1), TrkB, and TrkC as well as components of the MAPK and mammalian 
      target of rapamycin (mTOR) pathways. For confirmation, the impact of these hits 
      on gephyrin clustering was analyzed in rat primary hippocampal neurons. We found 
      that brain-derived neurotrophic factor (BDNF) acts on gephyrin clustering through 
      MAPK signaling, and this process may be controlled by the MAPK signaling 
      antagonist sprouty2. BDNF signaling through phosphatidylinositol 3-kinase 
      (PI3K)-Akt also activates mTOR and represses GSK3beta, which was previously shown to 
      reduce gephyrin clustering. Gephyrin is associated with inactive mTOR and becomes 
      released upon BDNF-dependent mTOR activation. In primary neurons, a reduction in 
      the number of gephyrin clusters due to manipulation of the BDNF-mTOR signaling is 
      associated with reduced GABA(A) receptor clustering, suggesting functional 
      impairment of GABA signaling. Accordingly, application of the mTOR antagonist 
      rapamycin leads to disinhibition of neuronal networks as measured on 
      microelectrode arrays. In conclusion, we provide evidence that BDNF regulates 
      gephyrin clustering via MAPK as well as PI3K-Akt-mTOR signaling.
FAU - Wuchter, Jennifer
AU  - Wuchter J
AD  - Department of Molecular Biology, Naturwissenschaftliches und Medizinisches 
      Institut an der Universitat Tubingen, 72770 Reutlingen, Germany.
FAU - Beuter, Simone
AU  - Beuter S
FAU - Treindl, Fridolin
AU  - Treindl F
FAU - Herrmann, Thoralf
AU  - Herrmann T
FAU - Zeck, Gunther
AU  - Zeck G
FAU - Templin, Markus F
AU  - Templin MF
FAU - Volkmer, Hansjurgen
AU  - Volkmer H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Carrier Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (gephyrin)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/biosynthesis/genetics/*metabolism
MH  - Gene Knockdown Techniques/methods
MH  - Genetic Testing/*methods
MH  - HeLa Cells
MH  - Humans
MH  - Membrane Proteins/biosynthesis/genetics/*metabolism
MH  - Mice
MH  - Multigene Family/*physiology
MH  - Primary Cell Culture
MH  - RNA, Small Interfering/*biosynthesis/genetics
MH  - Rats
MH  - Signal Transduction/*genetics
MH  - gamma-Aminobutyric Acid/physiology
PMC - PMC6621453
EDAT- 2012/10/19 06:00
MHDA- 2013/01/03 06:00
PMCR- 2013/04/17
CRDT- 2012/10/19 06:00
PHST- 2012/10/19 06:00 [entrez]
PHST- 2012/10/19 06:00 [pubmed]
PHST- 2013/01/03 06:00 [medline]
PHST- 2013/04/17 00:00 [pmc-release]
AID - 32/42/14821 [pii]
AID - 3804984 [pii]
AID - 10.1523/JNEUROSCI.1261-12.2012 [doi]
PST - ppublish
SO  - J Neurosci. 2012 Oct 17;32(42):14821-34. doi: 10.1523/JNEUROSCI.1261-12.2012.