NMDA Receptor Desensitization Regulated by Direct Binding to PDZ1-2 Domains of PSD-95

Autor: Alaa El-Husseini, Oana Cristina Vasuta, Bo Li, Christine Sutton, Lynn A. Raymond, Lily Y. J. Zhang, Lavan Sornarajah
Rok vydání: 2008
Předmět:
Patch-Clamp Techniques
Time Factors
Physiology
medicine.medical_treatment
Green Fluorescent Proteins
PDZ domain
Glycine
Transfection
Hippocampus
Receptors
N-Methyl-D-Aspartate
Article
Membrane Potentials
Phorbol Esters
mental disorders
medicine
Animals
Humans
Enzyme Inhibitors
Cells
Cultured
Protein kinase C
Desensitization (medicine)
Neurons
Analysis of Variance
Chemistry
musculoskeletal
neural
and ocular physiology
General Neuroscience
HEK 293 cells
Intracellular Signaling Peptides and Proteins
Glutamate receptor
Membrane Proteins
Embryo
Mammalian
Phosphoproteins
Protein Structure
Tertiary
Rats
Cell biology
2-Amino-5-phosphonovalerate
nervous system
Disks Large Homolog 4 Protein
Zonula Occludens-1 Protein
NMDA receptor
Excitatory Amino Acid Antagonists
Guanylate Kinases
Postsynaptic density
psychological phenomena and processes
Protein Binding
Zdroj: Journal of Neurophysiology. 99:3052-3062
ISSN: 1522-1598
0022-3077
DOI: 10.1152/jn.90301.2008
Popis: Regulation of N-methyl-d-aspartate receptor (NMDAR) activity by desensitization is important in physiological and pathological states; NMDAR desensitization contributes in shaping synaptic responses and may be protective by limiting calcium influx during sustained glutamate insults. We previously reported that glycine-independent desensitization decreases during hippocampal neuronal development, correlating with NMDAR synaptic localization and association with postsynaptic density 95 (PSD-95). PSD-95/Discs large/zona occludens (PDZ)-1,2 domains of PSD-95 bind to the C-terminus of NMDAR NR2 subunits. The role of PSD-95 in anchoring signaling proteins near NMDARs is well documented. To determine if PSD-95-induced changes in NMDAR desensitization occur because of direct binding to NR2 or due to recruitment of regulatory proteins, we tested the effects of various PSD-95 constructs on NMDAR currents in human embryonic kidney 293 (HEK293) cells and neurons. In HEK cells, wild-type PSD-95 significantly reduced wild-type NMDAR desensitization without altering currents of NMDARs containing NR2A-S1462A, a mutation that abolishes PSD-95 binding. The PSD-95 N-terminus truncated after the PDZ1-2 domains was sufficient for this effect in neurons with low endogenous PSD-95 levels; in NMDAR-expressing HEK cells, the effect persisted when PSD-95 multimerization was eliminated. Moreover other PSD-95 family members with highly homologous PDZ1-2 domains significantly reduced NMDAR desensitization. In mature neurons, disruption of PSD-95/NMDAR interaction through protein kinase C (PKC) activation increased desensitization to levels found in immature neurons, and this effect was not due to PKC direct regulation of NMDAR activity. We conclude that direct binding of PSD-95 increases stability of NMDAR responses to agonist exposure in neuronal and nonneuronal cells.
Databáze: OpenAIRE
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