PMID- 15312984
OWN - NLM
STAT- MEDLINE
DCOM- 20041006
LR  - 20161124
IS  - 0197-0186 (Print)
IS  - 0197-0186 (Linking)
VI  - 45
IP  - 6
DP  - 2004 Nov
TI  - Sequential activation of soluble guanylate cyclase, protein kinase G and 
      cGMP-degrading phosphodiesterase is necessary for proper induction of long-term 
      potentiation in CA1 of hippocampus. Alterations in hyperammonemia.
PG  - 895-901
AB  - Long-term potentiation (LTP) is a long-lasting enhancement of synaptic 
      transmission efficacy and is considered the base for some forms of learning and 
      memory. Nitric oxide (NO)-induced formation of cGMP is involved in hippocampal 
      LTP. We have studied in hippocampal slices the effects of application of a 
      tetanus to induce LTP on cGMP metabolism and the mechanisms by which cGMP 
      modulates LTP. Tetanus application induced a transient rise in cGMP, reaching a 
      maximum at 10s and decreasing below basal levels 5 min after the tetanus, 
      remaining below basal levels after 60 min. Soluble guanylate cyclase (sGC) 
      activity increased 5 min after tetanus and returned to basal levels at 60 min. 
      The decrease in cGMP was due to sustained tetanus-induced increase in 
      cGMP-degrading phosphodiesterase activity, which remained activated 60 min after 
      tetanus. Tetanus-induced activation of PDE and decrease of cGMP were prevented by 
      inhibiting protein kinase G (PKG). This indicates that the initial increase in 
      cGMP activates PKG that phosphorylates (and activates) cGMP-degrading PDE, which, 
      in turn, degrades cGMP. Inhibition of sGC, of PKG or of cGMP-degrading 
      phosphodiesterase impairs LTP, indicating that proper induction of LTP involves 
      transient activation of sGC and increase in cGMP, followed by activation of 
      cGMP-dependent protein kinase, which, in turn, activates cGMP-degrading 
      phosphodiesterase, resulting in long-lasting reduction of cGMP content. 
      Hyperammonemia is the main responsible for the neurological alterations found in 
      liver disease and hepatic encephalopathy, including impaired intellectual 
      function. Hyperammonemia impairs LTP in hippocampus by altering the modulation of 
      this sGC-PKG-cGMP-degrading PDE pathway. Exposure of hippocampal slices to 1 mM 
      ammonia completely prevents tetanus-induced decrease of cGMP by impairing 
      PKG-mediated activation of cGMP-degrading phosphodiesterase. This impairment is 
      responsible for the loss of the maintenance of LTP in hyperammonemia, and may be 
      also involved in the cognitive impairment in patients with hyperammonemia and 
      hepatic encephalopathy.
FAU - Monfort, Pilar
AU  - Monfort P
AD  - Laboratory of Neurobiology, Instituto de Investigaciones Citologicas, Fundacion 
      Valenciana de Investigaciones Biomedicas FVIB, Amadeo de Saboya 4, 46010 
      Valencia, Spain.
FAU - Munoz, Maria-Dolores
AU  - Munoz MD
FAU - Kosenko, Elena
AU  - Kosenko E
FAU - Llansola, Marta
AU  - Llansola M
FAU - Sanchez-Perez, Ana
AU  - Sanchez-Perez A
FAU - Cauli, Omar
AU  - Cauli O
FAU - Felipo, Vicente
AU  - Felipo V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - England
TA  - Neurochem Int
JT  - Neurochemistry international
JID - 8006959
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
RN  - EC 3.1.4.35 (3',5'-Cyclic-GMP Phosphodiesterases)
RN  - EC 4.6.1.2 (Guanylate Cyclase)
RN  - EC 4.6.1.2 (Soluble Guanylyl Cyclase)
SB  - IM
MH  - 3',5'-Cyclic-GMP Phosphodiesterases/*metabolism
MH  - Animals
MH  - Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Electric Stimulation
MH  - Enzyme Activation/physiology
MH  - Excitatory Postsynaptic Potentials/drug effects/physiology
MH  - Guanylate Cyclase
MH  - Hepatic Encephalopathy
MH  - Hippocampus/*drug effects
MH  - Humans
MH  - Hyperammonemia/enzymology/*metabolism
MH  - Long-Term Potentiation/*drug effects
MH  - Phosphodiesterase Inhibitors/pharmacology
MH  - Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors/*metabolism
MH  - Signal Transduction/drug effects
MH  - Soluble Guanylyl Cyclase
RF  - 38
EDAT- 2004/08/18 05:00
MHDA- 2004/10/07 09:00
CRDT- 2004/08/18 05:00
PHST- 2004/08/18 05:00 [pubmed]
PHST- 2004/10/07 09:00 [medline]
PHST- 2004/08/18 05:00 [entrez]
AID - S0197018604000683 [pii]
AID - 10.1016/j.neuint.2004.03.020 [doi]
PST - ppublish
SO  - Neurochem Int. 2004 Nov;45(6):895-901. doi: 10.1016/j.neuint.2004.03.020.