PMID- 22961271
OWN - NLM
STAT- MEDLINE
DCOM- 20130617
LR  - 20220309
IS  - 1522-1601 (Electronic)
IS  - 8750-7587 (Print)
IS  - 0161-7567 (Linking)
VI  - 113
IP  - 8
DP  - 2012 Oct 15
TI  - Phrenic long-term facilitation after acute intermittent hypoxia requires spinal 
      ERK activation but not TrkB synthesis.
PG  - 1184-93
LID - 10.1152/japplphysiol.00098.2012 [doi]
AB  - Acute intermittent hypoxia (AIH) elicits a form of spinal respiratory plasticity 
      known as phrenic long-term facilitation (pLTF). pLTF requires spinal serotonin 
      receptor-2 activation, the synthesis of new brain-derived neurotrophic factor 
      (BDNF), and the activation of its high-affinity receptor tyrosine kinase, TrkB. 
      Spinal adenosine 2A receptor activation elicits a distinct pathway to phrenic 
      motor facilitation (pMF); this BDNF synthesis-independent pathway instead 
      requires new synthesis of an immature TrkB isoform. Since hypoxia increases 
      extracellular adenosine levels, we tested the hypothesis that new synthesis of 
      TrkB and BDNF contribute to AIH-induced pLTF. Furthermore, given that signaling 
      mechanisms "downstream" from TrkB are unknown in either mechanism, we tested the 
      hypothesis that pLTF requires MEK/ERK and/or phosphatidylinositol 3-kinase 
      (PI3K)/Akt activation. In anesthetized Sprague-Dawley rats, an intrathecal 
      catheter at cervical level 4 was used to deliver drugs near the phrenic motor 
      nucleus. Since pLTF was blocked by spinal injections of small interfering RNAs 
      targeting BDNF mRNA but not TrkB mRNA, only new BDNF synthesis is required for 
      AIH-induced pLTF. Pretreatment with a MEK inhibitor (U0126) blocked pLTF, whereas 
      a PI3K inhibitor (PI-828) had no effect. Thus, AIH-induced pLTF requires MEK/ERK 
      (not PI3K/AKT) signaling pathways. When U0126 was injected post-AIH, pLTF 
      development was halted but not reversed, suggesting that ERK is critical for the 
      development but not maintenance of pLTF. Thus, there are clear mechanistic 
      distinctions between AIH-induced pLTF (i.e., BDNF synthesis and MEK/ERK 
      dependent) versus adenosine 2A receptor-induced pMF (i.e., TrkB synthesis and 
      PI3K/Akt dependent).
FAU - Hoffman, M S
AU  - Hoffman MS
AD  - Department of Comparative Biosciences, University of Wisconsin, 2015 Linden 
      Drive, Madison, WI 53706-1102, USA.
FAU - Nichols, N L
AU  - Nichols NL
FAU - Macfarlane, P M
AU  - Macfarlane PM
FAU - Mitchell, G S
AU  - Mitchell GS
LA  - eng
GR  - R01 HL080209/HL/NHLBI NIH HHS/United States
GR  - HL-092785/HL/NHLBI NIH HHS/United States
GR  - T32 HL007654/HL/NHLBI NIH HHS/United States
GR  - F31 HL092785/HL/NHLBI NIH HHS/United States
GR  - HL-080209/HL/NHLBI NIH HHS/United States
GR  - T32-HL-007654/HL/NHLBI NIH HHS/United States
GR  - T32 GM008692/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120906
PL  - United States
TA  - J Appl Physiol (1985)
JT  - Journal of applied physiology (Bethesda, Md. : 1985)
JID - 8502536
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Butadienes)
RN  - 0 (Nitriles)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Adenosine A2)
RN  - 0 (U 0126)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Blood Gas Analysis/methods
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism
MH  - Butadienes/pharmacology
MH  - Hypoxia/enzymology/genetics/*metabolism/physiopathology
MH  - Injections, Spinal/methods
MH  - Long-Term Potentiation/drug effects/genetics/*physiology
MH  - MAP Kinase Signaling System/drug effects/*genetics
MH  - Male
MH  - Neuronal Plasticity/drug effects/genetics/physiology
MH  - Nitriles/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phrenic Nerve/drug effects/metabolism/*physiology
MH  - RNA, Messenger/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkB/*biosynthesis/genetics/metabolism
MH  - Receptors, Adenosine A2/genetics/metabolism
MH  - Respiratory System/drug effects/metabolism/physiopathology
MH  - Signal Transduction
MH  - Spinal Cord/drug effects/metabolism/physiology
PMC - PMC3472488
EDAT- 2012/09/11 06:00
MHDA- 2013/06/19 06:00
PMCR- 2013/10/15
CRDT- 2012/09/11 06:00
PHST- 2012/09/11 06:00 [entrez]
PHST- 2012/09/11 06:00 [pubmed]
PHST- 2013/06/19 06:00 [medline]
PHST- 2013/10/15 00:00 [pmc-release]
AID - japplphysiol.00098.2012 [pii]
AID - JAPPL-00098-2012 [pii]
AID - 10.1152/japplphysiol.00098.2012 [doi]
PST - ppublish
SO  - J Appl Physiol (1985). 2012 Oct 15;113(8):1184-93. doi: 
      10.1152/japplphysiol.00098.2012. Epub 2012 Sep 6.