PMID- 22699894
OWN - NLM
STAT- MEDLINE
DCOM- 20120924
LR  - 20211203
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 32
IP  - 24
DP  - 2012 Jun 13
TI  - Brain-derived neurotrophic factor activation of CaM-kinase kinase via transient 
      receptor potential canonical channels induces the translation and synaptic 
      incorporation of GluA1-containing calcium-permeable AMPA receptors.
PG  - 8127-37
LID - 10.1523/JNEUROSCI.6034-11.2012 [doi]
AB  - Glutamatergic synapses in early postnatal development transiently express 
      calcium-permeable AMPA receptors (CP-AMPARs). Although these GluA2-lacking 
      receptors are essential and are elevated in response to brain-derived 
      neurotrophic factor (BDNF), little is known regarding molecular mechanisms that 
      govern their expression and synaptic insertion. Here we show that BDNF-induced 
      GluA1 translation in rat primary hippocampal neurons requires the activation of 
      mammalian target of rapamycin (mTOR) via calcium calmodulin-dependent protein 
      kinase kinase (CaMKK). Specifically, BDNF-mediated phosphorylation of threonine 
      308 (T308) in AKT, a known substrate of CaMKK and an upstream activator of 
      mTOR-dependent translation, was prevented by (1) pharmacological inhibition of 
      CaMKK with STO-609, (2) overexpression of a dominant-negative CaMKK, or (3) short 
      hairpin-mediated knockdown of CaMKK. GluA1 surface expression induced by BDNF, as 
      assessed by immunocytochemistry using an extracellular N-terminal GluA1 antibody 
      or by surface biotinylation, was impaired following knockdown of CaMKK or 
      treatment with STO-609. Activation of CaMKK by BDNF requires transient receptor 
      potential canonical (TRPC) channels as SKF-96365, but not the NMDA receptor 
      antagonist d-APV, prevented BDNF-induced GluA1 surface expression as well as 
      phosphorylation of CaMKI, AKT(T308), and mTOR. Using siRNA we confirmed the 
      involvement of TRPC5 and TRPC6 subunits in BDNF-induced AKT(T308) 
      phosphorylation. The BDNF-induced increase in mEPSC was blocked by IEM-1460, a 
      selected antagonist of CP-AMPARs, as well as by the specific repression of acute 
      GluA1 translation via siRNA to GluA1 but not GluA2. Together these data support 
      the conclusion that newly synthesized GluA1 subunits, induced by BDNF, are 
      readily incorporated into synapses where they enhance the expression of CP-AMPARs 
      and synaptic strength.
FAU - Fortin, Dale A
AU  - Fortin DA
AD  - Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, 
      USA. fortind@ohsu.edu
FAU - Srivastava, Taasin
AU  - Srivastava T
FAU - Dwarakanath, Diya
AU  - Dwarakanath D
FAU - Pierre, Philippe
AU  - Pierre P
FAU - Nygaard, Sean
AU  - Nygaard S
FAU - Derkach, Victor A
AU  - Derkach VA
FAU - Soderling, Thomas R
AU  - Soderling TR
LA  - eng
GR  - R01 NS027037/NS/NINDS NIH HHS/United States
GR  - NS027037/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Benzimidazoles)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Calcium Channel Blockers)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (IEM 1460)
RN  - 0 (Imidazoles)
RN  - 0 (Naphthalimides)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, AMPA)
RN  - 0 (STO 609)
RN  - 0 (TRPC Cation Channels)
RN  - 0 (Trpc5 protein, rat)
RN  - 0 (Trpc6 protein, rat)
RN  - 76726-92-6 (2-Amino-5-phosphonovalerate)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase)
RN  - I61V87164A (1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole)
RN  - PJY633525U (Adamantane)
RN  - TFZ3H25BS1 (glutamate receptor ionotropic, AMPA 1)
SB  - IM
MH  - 2-Amino-5-phosphonovalerate/pharmacology
MH  - Adamantane/analogs & derivatives/pharmacology
MH  - Animals
MH  - Benzimidazoles/pharmacology
MH  - Brain-Derived Neurotrophic Factor/*physiology
MH  - Calcium Channel Blockers/pharmacology
MH  - Calcium-Calmodulin-Dependent Protein Kinase Kinase/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Excitatory Amino Acid Antagonists/pharmacology
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Hippocampus/drug effects/metabolism/physiology
MH  - Imidazoles/pharmacology
MH  - Male
MH  - Miniature Postsynaptic Potentials/drug effects/physiology
MH  - Naphthalimides/pharmacology
MH  - Neurons/drug effects/metabolism
MH  - Primary Cell Culture
MH  - RNA, Small Interfering/administration & dosage/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, AMPA/*metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - TRPC Cation Channels/genetics/*physiology
PMC - PMC3390208
MID - NIHMS385665
EDAT- 2012/06/16 06:00
MHDA- 2012/09/25 06:00
PMCR- 2012/12/13
CRDT- 2012/06/16 06:00
PHST- 2012/06/16 06:00 [entrez]
PHST- 2012/06/16 06:00 [pubmed]
PHST- 2012/09/25 06:00 [medline]
PHST- 2012/12/13 00:00 [pmc-release]
AID - 32/24/8127 [pii]
AID - 3780633 [pii]
AID - 10.1523/JNEUROSCI.6034-11.2012 [doi]
PST - ppublish
SO  - J Neurosci. 2012 Jun 13;32(24):8127-37. doi: 10.1523/JNEUROSCI.6034-11.2012.