Propofol inhibits phosphorylation of N-methyl-D-aspartate receptor NR1 subunits in neurons.
BACKGROUND
Anesthetics may interact with ionotropic glutamate receptors to produce some of their biologic actions. Cellular studies reveal that the ionotropic glutamate receptors, N-methyl-D-aspartate receptors (NMDARs), can be phosphorylated on their NR1 subunits at the C-terminal serine residues, which is a major mechanism for the regulation of NMDAR functions. It is currently unknown whether anesthetics have any modulatory effects on NMDAR NR1 subunit phosphorylation.


METHODS
The possible effect of a general anesthetic propofol on phosphorylation of NR1 subunits at serine 897 (pNR1S897) and 896 (pNR1S896) was detected in cultured rat cortical neurons.


RESULTS
Propofol consistently reduced basal levels of pNR1S897 and pNR1S896 in a concentration-dependent manner. This reduction was rapid as the reliable reduction of pNR1S896 developed 1 min after propofol administration. Pretreatment of cultures with the protein phosphatase 2A inhibitors okadaic acid or calyculin A blocked the effect of propofol on the NR1 phosphorylation, whereas okadaic acid or calyculin A alone did not alter basal pNR1S897 and pNR1S896 levels. In addition, propofol decreased tyrosine phosphorylation of protein phosphatase 2A at tyrosine 307, resulting in an increase in protein phosphatase 2A activity. In the presence of propofol, the NMDAR agonist-induced intracellular Ca2+ increase was impaired in neurons with dephosphorylated NR1 subunits.


CONCLUSIONS
Together, these data indicate an inhibitory effect of a general anesthetic propofol on NMDAR NR1 subunit phosphorylation in neurons. This inhibition was mediated through a signaling mechanism involving activation of protein phosphatase 2A.
Kingston
Seth
S
Department of Anesthesiology, University of Missouri-Kansas City School of Medicine, Saint Luke's Hospital, Kansas City, Missouri 64108, USA.
Mao
Limin
L
Yang
Lu
L
Arora
Anish
A
Fibuch
Eugene E
EE
Wang
John Q
JQ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D008387:Marine Toxins; D009474:Neurons / Q000187:drug effects*; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010766:Phosphorylation; D015742:Propofol / Q000494:pharmacology*; D054648:Protein Phosphatase 2; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D008387:Marine Toxins; C409466:NR1 NMDA receptor; D010080:Oxazoles; D016194:Receptors, N-Methyl-D-Aspartate; D019319:Okadaic Acid; D014443:Tyrosine; D012694:Serine; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D002118:Calcium; D015742:Propofol