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1.
J Neurosci ; 29(38): 11965-72, 2009 Sep 23.
Article in English | MEDLINE | ID: mdl-19776282

ABSTRACT

Phosphorylation of the NR1 subunit of NMDA receptors (NMDARs) at serine (S) 897 is markedly reduced in schizophrenia patients. However, the role of NR1 S897 phosphorylation in normal synaptic function and adaptive behaviors are unknown. To address these questions, we generated mice in which the NR1 S897 is replaced with alanine (A). This knock-in mutation causes severe impairment in NMDAR synaptic incorporation and NMDAR-mediated synaptic transmission. Furthermore, the phosphomutant animals have reduced AMPA receptor (AMPAR)-mediated synaptic transmission, decreased AMPAR GluR1 subunit in the synapse, and impaired long-term potentiation. Finally, the mutant mice exhibit behavioral deficits in social interaction and sensorimotor gating. Our results suggest that an impairment in NR1 phosphorylation leads to glutamatergic hypofunction that can contribute to behavioral deficits associated with psychiatric disorders.


Subject(s)
Behavior, Animal/physiology , Neuronal Plasticity , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Brain/physiology , Brain/ultrastructure , Gene Knock-In Techniques , In Vitro Techniques , Long-Term Potentiation/genetics , Long-Term Potentiation/physiology , Male , Mice , Mice, Inbred C57BL , Mutation, Missense , Neuronal Plasticity/genetics , Neurons/physiology , Neurons/ultrastructure , Phosphorylation , Receptors, AMPA/metabolism , Schizophrenia/genetics , Social Behavior , Synapses/genetics , Synapses/physiology , Synapses/ultrastructure , Synaptic Transmission/genetics , Synaptic Transmission/physiology
2.
Cancer Res ; 65(23): 11061-70, 2005 Dec 01.
Article in English | MEDLINE | ID: mdl-16322256

ABSTRACT

Radiation-induced inhibition of rapamycin-sensitive pathway and its effect on the cellular response to radiation were studied in the human breast cancer cell line MCF-7. Both radiation and rapamycin shared molecular targets and induced similar physiologic responses. Each of these treatments increased immunostaining of mammalian target of rapamycin (mTOR) in the nucleus, and radiation led to decreased phosphorylation of its autophosphorylation site Ser2481. In addition to dephosphorylation of established mTOR downstream effectors 4E-binding protein 1 and p70 ribosomal S6 kinase, both treatments decreased the level of eukaryotic initiation factor 4G. Experiments with the potentiometric dye, JC-1, revealed an oligomycin-dependent increase in mitochondrial membrane potential following radiation or rapamycin treatment, suggesting that both lead to reversal of F0F1ATPase activity. Both radiation and rapamycin induced sequestration of cytoplasmic material in autophagic vacuoles. In both cases, appearance of autophagic vacuoles involved the participation of microtubule-associated protein 1 light chain 3 (LC3). Transient cotransfection of green fluorescent protein-LC3 with either wild-type or dominant-negative mTOR further showed that inactivation of mTOR pathway is sufficient to induce autophagy in these cells. Finally, administration of rapamycin in combination with radiation led to enhanced mitochondria hyperpolarization, p53 phosphorylation, and increased cell death. Taken together, these experiments show that radiation-induced inhibition of rapamycin-sensitive pathway in MCF-7 cells causes changes in mitochondria metabolism, development of autophagy, and an overall decrease in cell survival.


Subject(s)
Autophagy/radiation effects , Breast Neoplasms/radiotherapy , Mitochondria/radiation effects , Protein Kinases/metabolism , Sirolimus/pharmacology , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenocarcinoma/radiotherapy , Antibiotics, Antineoplastic/antagonists & inhibitors , Antibiotics, Antineoplastic/pharmacology , Autophagy/drug effects , Autophagy/physiology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Cell Survival/radiation effects , Cytoplasm/enzymology , Cytoplasm/metabolism , Humans , Intracellular Membranes/drug effects , Intracellular Membranes/physiology , Intracellular Membranes/radiation effects , Intracellular Signaling Peptides and Proteins/pharmacology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , Mitochondria/drug effects , Mitochondria/physiology , Phosphorylation/radiation effects , Sirolimus/antagonists & inhibitors , TOR Serine-Threonine Kinases , Tumor Suppressor Protein p53/metabolism , Vacuoles/enzymology , Vacuoles/metabolism
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