Modulation of NMDA receptors by AKT kinase.
The aim of the present work was to assess whether Akt modulates NMDA receptor function in cerebellar neurons in culture. Forskolin increases cAMP and activates Akt and NMDA receptors. In neurons treated with forskolin, intracellular calcium increased to 296 +/- 38% and this was completely prevented by inhibition of Akt. This indicates that, in these neurons, cAMP modulates NMDA receptors via Epac and Akt. Brain derived neurotrophic factor (BDNF) increases phosphorylation (and activity) of Akt to 350 +/- 60% of basal and also potentiates the increase of calcium and in cGMP induced by NMDA. BDNF-induced potentiation of NMDA receptor function is completely prevented by inhibition of PI3 kinase or of Akt. This indicates that BDNF modulates NMDA receptor function via PI3 kinase and Akt. Activation of NMDA receptors also leads to phosphorylation and activation of Akt which, in turn, potentiates NMDA receptor activation. The results reported indicate that when Akt activity increases the activation of NMDA receptors by its agonists also increases. Akt may play important roles in the modulation of NMDA receptor responses by other neurotransmitters and modulators and in the adaptation of NMDA receptor function to the physiological environmental conditions.
Sánchez-Pérez
Ana María
AM
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Llansola
Marta
M
Felipo
Vicente
V
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005576:Colforsin / Q000494:pharmacology; D006152:Cyclic GMP / Q000737:chemistry / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D015151:Immunoblotting; D047468:Immunoprecipitation; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; C409466:NR1 NMDA receptor; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D005576:Colforsin; D016202:N-Methylaspartate; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP; D002118:Calcium