PMID- 25615535
OWN - NLM
STAT- MEDLINE
DCOM- 20150821
LR  - 20181113
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1850
IP  - 4
DP  - 2015 Apr
TI  - The Nav1.2 channel is regulated by GSK3.
PG  - 832-44
LID - S0304-4165(15)00031-8 [pii]
LID - 10.1016/j.bbagen.2015.01.011 [doi]
AB  - BACKGROUND: Phosphorylation plays an essential role in regulating voltage-gated 
      sodium (Na(v)) channels and excitability. Yet, a surprisingly limited number of 
      kinases have been identified as regulators of Na(v) channels. We posited that 
      glycogen synthase kinase 3 (GSK3), a critical kinase found associated with 
      numerous brain disorders, might directly regulate neuronal Na(v) channels. 
      METHODS: We used patch-clamp electrophysiology to record sodium currents from 
      Na(v)1.2 channels stably expressed in HEK-293 cells. mRNA and protein levels were 
      quantified with RT-PCR, Western blot, or confocal microscopy, and in vitro 
      phosphorylation and mass spectrometry to identify phosphorylated residues. 
      RESULTS: We found that exposure of cells to GSK3 inhibitor XIII significantly 
      potentiates the peak current density of Na(v)1.2, a phenotype reproduced by 
      silencing GSK3 with siRNA. Contrarily, overexpression of GSK3beta suppressed 
      Na(v)1.2-encoded currents. Neither mRNA nor total protein expression was changed 
      upon GSK3 inhibition. Cell surface labeling of CD4-chimeric constructs expressing 
      intracellular domains of the Na(v)1.2 channel indicates that cell surface 
      expression of CD4-Na(v)1.2 C-tail was up-regulated upon pharmacological 
      inhibition of GSK3, resulting in an increase of surface puncta at the plasma 
      membrane. Finally, using in vitro phosphorylation in combination with high 
      resolution mass spectrometry, we further demonstrate that GSK3beta phosphorylates 
      T(1966) at the C-terminal tail of Na(v)1.2. CONCLUSION: These findings provide 
      evidence for a new mechanism by which GSK3 modulates Na(v) channel function via 
      its C-terminal tail. GENERAL SIGNIFICANCE: These findings provide fundamental 
      knowledge in understanding signaling dysfunction common in several 
      neuropsychiatric disorders.
CI  - Published by Elsevier B.V.
FAU - James, Thomas F
AU  - James TF
AD  - Department of Pharmacology & Toxicology, USA; Neuroscience Graduate Program, USA.
FAU - Nenov, Miroslav N
AU  - Nenov MN
AD  - Department of Pharmacology & Toxicology, USA.
FAU - Wildburger, Norelle C
AU  - Wildburger NC
AD  - Department of Pharmacology & Toxicology, USA; Neuroscience Graduate Program, USA.
FAU - Lichti, Cheryl F
AU  - Lichti CF
AD  - Department of Pharmacology & Toxicology, USA.
FAU - Luisi, Jonathan
AU  - Luisi J
AD  - Department of Pharmacology & Toxicology, USA.
FAU - Vergara, Fernanda
AU  - Vergara F
AD  - Department of Pharmacology & Toxicology, USA.
FAU - Panova-Electronova, Neli I
AU  - Panova-Electronova NI
AD  - Department of Pharmacology & Toxicology, USA.
FAU - Nilsson, Carol L
AU  - Nilsson CL
AD  - Department of Pharmacology & Toxicology, USA.
FAU - Rudra, Jai S
AU  - Rudra JS
AD  - Department of Pharmacology & Toxicology, USA.
FAU - Green, Thomas A
AU  - Green TA
AD  - Department of Pharmacology & Toxicology, USA; Center for Addiction Research, USA.
FAU - Labate, Demetrio
AU  - Labate D
AD  - Department of Mathematics, University of Houston, USA.
FAU - Laezza, Fernanda
AU  - Laezza F
AD  - Department of Pharmacology & Toxicology, USA; Center for Addiction Research, USA; 
      Center for Biomedical Engineering, USA; Mitchell Center for Neurodegenerative 
      Diseases, USA. Electronic address: felaezza@utmb.edu.
LA  - eng
GR  - R01 MH095995/MH/NIMH NIH HHS/United States
GR  - T32 ES007254/ES/NIEHS NIH HHS/United States
GR  - NIMH 0955995/PHS HHS/United States
GR  - T32ES007254/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150120
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (NAV1.2 Voltage-Gated Sodium Channel)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Amino Acid Sequence
MH  - Glycogen Synthase Kinase 3/antagonists & inhibitors/*physiology
MH  - HEK293 Cells
MH  - Humans
MH  - Molecular Sequence Data
MH  - NAV1.2 Voltage-Gated Sodium Channel/chemistry/*physiology
MH  - Phosphorylation
PMC - PMC4336163
MID - NIHMS662046
OTO - NOTNLM
OT  - Confocal microscopy
OT  - Glycogen synthase kinase 3
OT  - Patch-clamp electrophysiology
OT  - Protein-protein interactions
OT  - Sodium channel
EDAT- 2015/01/24 06:00
MHDA- 2015/08/22 06:00
PMCR- 2016/04/01
CRDT- 2015/01/24 06:00
PHST- 2014/07/21 00:00 [received]
PHST- 2014/12/17 00:00 [revised]
PHST- 2015/01/14 00:00 [accepted]
PHST- 2015/01/24 06:00 [entrez]
PHST- 2015/01/24 06:00 [pubmed]
PHST- 2015/08/22 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - S0304-4165(15)00031-8 [pii]
AID - 10.1016/j.bbagen.2015.01.011 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2015 Apr;1850(4):832-44. doi: 10.1016/j.bbagen.2015.01.011. 
      Epub 2015 Jan 20.