PMID- 18660503
OWN - NLM
STAT- MEDLINE
DCOM- 20081110
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 39
DP  - 2008 Sep 26
TI  - Nerve growth factor inhibits Na+/H+ exchange and formula absorption through 
      parallel phosphatidylinositol 3-kinase-mTOR and ERK pathways in thick ascending 
      limb.
PG  - 26602-11
LID - 10.1074/jbc.M803019200 [doi]
AB  - In the medullary thick ascending limb, inhibiting the basolateral NHE1 Na(+)/H(+) 
      exchanger with nerve growth factor (NGF) induces actin cytoskeleton remodeling 
      that secondarily inhibits apical NHE3 and transepithelial HCO(3)(-) absorption. 
      The inhibition by NGF is mediated 50% through activation of extracellular 
      signal-regulated kinase (ERK). Here we examined the signaling pathway responsible 
      for the remainder of the NGF-induced inhibition. Inhibition of HCO(3)(-) 
      absorption was reduced 45% by the phosphatidylinositol 3-kinase (PI3K) inhibitors 
      wortmannin or LY294002 and 50% by rapamycin, a specific inhibitor of mammalian 
      target of rapamycin (mTOR), a downstream effector of PI3K. The combination of a 
      PI3K inhibitor plus rapamycin did not cause a further reduction in the inhibition 
      by NGF. In contrast, the combination of a PI3K inhibitor plus the MEK/ERK 
      inhibitor U0126 completely eliminated inhibition by NGF. Rapamycin decreased 
      NGF-induced inhibition of basolateral NHE1 by 45%. NGF induced a 2-fold increase 
      in phosphorylation of Akt, a PI3K target linked to mTOR activation, and a 
      2.2-fold increase in the activity of p70 S6 kinase, a downstream effector of 
      mTOR. p70 S6 kinase activation was blocked by wortmannin and rapamycin, 
      consistent with PI3K, mTOR, and p70 S6 kinase in a linear pathway. 
      Rapamycin-sensitive inhibition of NHE1 by NGF was associated with an increased 
      level of phosphorylated mTOR in the basolateral membrane domain. These findings 
      indicate that NGF inhibits HCO(3)(-) absorption in the medullary thick ascending 
      limb through the parallel activation of PI3K-mTOR and ERK signaling pathways, 
      which converge to inhibit NHE1. The results identify a role for mTOR in the 
      regulation of Na(+)/H(+) exchange activity and implicate NHE1 as a possible 
      downstream effector contributing to mTOR's effects on cell growth, proliferation, 
      survival, and tumorigenesis.
FAU - Good, David W
AU  - Good DW
AD  - Departments of Medicine, The University of Texas Medical Branch, Galveston, Texas 
      77555, USA. dgood@utmb.edu
FAU - George, Thampi
AU  - George T
FAU - Watts, Bruns A 3rd
AU  - Watts BA 3rd
LA  - eng
GR  - R01-DK-038217/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080725
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Bicarbonates)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Slc9a1 protein, rat)
RN  - 0 (Slc9a3 protein, rat)
RN  - 0 (Sodium-Hydrogen Exchanger 1)
RN  - 0 (Sodium-Hydrogen Exchanger 3)
RN  - 0 (Sodium-Hydrogen Exchangers)
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Absorption/drug effects
MH  - Animals
MH  - Bicarbonates/*metabolism
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/*metabolism
MH  - MAP Kinase Signaling System/*drug effects
MH  - Male
MH  - Nerve Growth Factor/metabolism/*pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism
MH  - Rats
MH  - Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors/metabolism
MH  - Sodium-Hydrogen Exchanger 1
MH  - Sodium-Hydrogen Exchanger 3
MH  - Sodium-Hydrogen Exchangers/antagonists & inhibitors/*metabolism
MH  - TOR Serine-Threonine Kinases
PMC - PMC2546562
EDAT- 2008/07/29 09:00
MHDA- 2008/11/11 09:00
PMCR- 2009/09/26
CRDT- 2008/07/29 09:00
PHST- 2008/07/29 09:00 [pubmed]
PHST- 2008/11/11 09:00 [medline]
PHST- 2008/07/29 09:00 [entrez]
PHST- 2009/09/26 00:00 [pmc-release]
AID - S0021-9258(20)52404-6 [pii]
AID - 26602 [pii]
AID - 10.1074/jbc.M803019200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Sep 26;283(39):26602-11. doi: 10.1074/jbc.M803019200. Epub 2008 
      Jul 25.