Increased expression of neuronal Src and tyrosine phosphorylation of NMDA receptors in rat brain after systemic treatment with MK-801.
We have observed that systemic treatment with the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 increases Src expression and NMDA receptor phosphorylation in rat brain. A partial cDNA encoding rat neuronal Src was isolated and its sequence was used to design specific oligonucleotide probes. Systemically administered MK-801 (5 mg/kg for 4 h) increased by 28+/-4% mRNA expression of neuronal Src in the superficial layers of the parietal cortex. This effect was observed at doses as low as 0.2 mg/kg. A similar, although more modest, induction was observed 6 h after phencyclidine (15 mg/kg) administration, but not after high doses of memantine and ketamine. The MK-801-induced effect was not blocked by pretreatment with clozapine. Consistent with the increase in mRNA levels, cortical Src protein was increased to 186 +/- 24% of control 24 h after MK-801 treatment. Total cellular Src activity was also increased in parietal cortex homogenates 4 h after MK-801 (5 mg/kg). Moreover, MK-801 treatment (0.5 mg/kg and 5 mg/kg for 4 h) increased tyrosine phosphorylation, but not protein levels, of the NMDA receptor subunit NR2A. These results provide evidence for a contribution of Src and tyrosine phosphorylation of NMDA receptors in the pharmacological actions of uncompetitive NMDA receptor antagonists.
A.I. Virtanen Institute, University of Kuopio, P.O.B. 1627, 70211 Kuopio, Finland.
A
A
Lindén
M
M
Storvik
M
M
Lakso
A
A
Haapasalo
D
D
Lee
J M
JM
Witkin
Y
Y
Sei
E
E
Castrén
G
G
Wong
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009474:Neurons / Q000201:enzymology; D010622:Phencyclidine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D021122:Protein Subunits; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
D018076:DNA, Complementary; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D021122:Protein Subunits; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine; D007649:Ketamine; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D019061:src-Family Kinases; D010622:Phencyclidine