The cellular Na+ pump as a site of action for carbon monoxide and glutamate: a mechanism for long-term modulation of cellular activity.
Carbon monoxide (CO) induces a long-lasting alteration in cerebellar alpha 3-Na,K-ATPase independent of [Na+] but linked to cGMP synthesis and localized to Purkinje neurons. The action of CO is absent in Purkinje neuron-deficient mice, mimicked by 8-Br-cGMP, and blocked by inhibition of PKG. Glutamate (Glu) and metabotropic agonists mimic the action of CO, an effect that requires PKC and is associated with CO synthesis. These data suggest that CO regulates Na,K-ATPase through cGMP and PKG, and that Glu regulates CO through mGluRs. This system is also modulated by NMDA agonists and nitric oxide, possibly via Glu release, as well as by free radicals. These findings offer a mechanism by which CO, Glu, and free radicals can exert specific effects on synaptic transmission (relevant to long-term changes in cell excitability), as well as more general actions on energy metabolism (relevant to the pathophysiology of excitotoxicity).
Nathanson
J A
JA
Neuropharmacology Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Boston 02114, USA.
Scavone
C
C
Scanlon
C
C
McKee
M
M
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D002531:Cerebellum / Q000201:enzymology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation; D005609:Free Radicals; D018698:Glutamic Acid / Q000494:pharmacology*; D006706:Homeostasis; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011689:Purkinje Cells / Q000201:enzymology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D005609:Free Radicals; D018094:Receptors, Metabotropic Glutamate; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D018698:Glutamic Acid; D002248:Carbon Monoxide; D011494:Protein Kinases; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP