PMID- 24184018
OWN - NLM
STAT- MEDLINE
DCOM- 20140130
LR  - 20211021
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Print)
IS  - 0014-4886 (Linking)
VI  - 250
DP  - 2013 Dec
TI  - Endogenous PI3K/Akt and NMDAR act independently in the regulation of CREB 
      activity in lumbosacral spinal cord in cystitis.
PG  - 366-75
LID - 10.1016/j.expneurol.2013.10.015 [doi]
AB  - The integral interaction of signaling components in the regulation of visceral 
      inflammation-induced central sensitization in the spinal cord has not been well 
      studied. Here we report that phosphoinositide 3-kinase (PI3K)-dependent Akt 
      activation and N-methyl-d-aspartic acid receptor (NMDAR) in lumbosacral spinal 
      cord independently regulate the activation of cAMP response element-binding 
      protein (CREB) in vivo in a rat visceral pain model of cystitis induced by 
      intraperitoneal injection of cyclophosphamide (CYP). We demonstrate that 
      suppression of endogenous PI3K/Akt activity with a potent PI3K inhibitor LY294002 
      reverses CYP-induced phosphorylation of CREB, however, it has no effect on 
      CYP-induced phosphorylation of NR1 at Ser(897) and Ser(896); conversely, 
      inhibition of NMDAR in vivo with MK801 fails to block CYP-induced Akt activation 
      but significantly attenuates CYP-induced CREB phosphorylation in lumbosacral 
      spinal cord. This novel interrelationship of PI3K/Akt, NMDAR, and CREB activation 
      in lumbosacral spinal cord is further confirmed in an ex vivo spinal slice 
      culture system exposed to an excitatory neurotransmitter calcitonin gene-related 
      peptide (CGRP). Consistently we found that CGRP-triggered CREB activation can be 
      blocked by both PI3K inhibitor LY294002 and NMDAR antagonists MK801 and D-AP5. 
      However, CGRP-triggered Akt activation cannot be blocked by MK801 or D-AP5; vice 
      versa, LY294002 pretreatment that suppresses the Akt activity fails to reverse 
      CGRP-elicited NR1 phosphorylation. These results suggest that PI3K/Akt and NMDAR 
      independently regulate spinal plasticity in visceral pain model, and target of a 
      single pathway is necessary but not sufficient in treatment of visceral 
      hypersensitivity.
CI  - (c) 2013.
FAU - Kay, Jarren C
AU  - Kay JC
AD  - Department of Physiology and Biophysics, Virginia Commonwealth University School 
      of Medicine, Richmond, Virginia.
FAU - Xia, Chun-Mei
AU  - Xia CM
AD  - Department of Physiology and Biophysics, Virginia Commonwealth University School 
      of Medicine, Richmond, Virginia.
FAU - Liu, Miao
AU  - Liu M
AD  - Department of Physiology and Biophysics, Virginia Commonwealth University School 
      of Medicine, Richmond, Virginia.
FAU - Shen, Shanwei
AU  - Shen S
AD  - Department of Physiology and Biophysics, Virginia Commonwealth University School 
      of Medicine, Richmond, Virginia.
FAU - Yu, Sharon J
AU  - Yu SJ
AD  - Department of Physiology and Biophysics, Virginia Commonwealth University School 
      of Medicine, Richmond, Virginia.
FAU - Chung, Chulwon
AU  - Chung C
AD  - Department of Physiology and Biophysics, Virginia Commonwealth University School 
      of Medicine, Richmond, Virginia.
FAU - Qiao, Li-Ya
AU  - Qiao LY
AD  - Department of Physiology and Biophysics, Virginia Commonwealth University School 
      of Medicine, Richmond, Virginia.
LA  - eng
GR  - R01 DK077917/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20131030
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Central Nervous System Sensitization/*physiology
MH  - Cyclic AMP Response Element-Binding Protein/*metabolism
MH  - Cystitis/*metabolism/physiopathology
MH  - Disease Models, Animal
MH  - Immunohistochemistry
MH  - Lumbosacral Region
MH  - Male
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Signal Transduction/physiology
MH  - Spinal Cord/*metabolism
PMC - PMC3878196
MID - NIHMS536515
OTO - NOTNLM
OT  - Akt
OT  - CREB
OT  - Central sensitization
OT  - NMDAR
OT  - Spinal cord
EDAT- 2013/11/05 06:00
MHDA- 2014/01/31 06:00
PMCR- 2014/12/01
CRDT- 2013/11/05 06:00
PHST- 2013/06/21 00:00 [received]
PHST- 2013/10/15 00:00 [revised]
PHST- 2013/10/22 00:00 [accepted]
PHST- 2013/11/05 06:00 [entrez]
PHST- 2013/11/05 06:00 [pubmed]
PHST- 2014/01/31 06:00 [medline]
PHST- 2014/12/01 00:00 [pmc-release]
AID - 10.1016/j.expneurol.2013.10.015 [doi]
PST - ppublish
SO  - Exp Neurol. 2013 Dec;250:366-75. doi: 10.1016/j.expneurol.2013.10.015. Epub 2013 
      Oct 30.