PMID- 25544544
OWN - NLM
STAT- MEDLINE
DCOM- 20150414
LR  - 20181113
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 54
IP  - 3
DP  - 2015 Jan 27
TI  - Heteromerization of ligand binding domains of N-methyl-D-aspartate receptor 
      requires both coagonists, L-glutamate and glycine.
PG  - 787-94
LID - 10.1021/bi501437s [doi]
AB  - NMDA receptors (NMDAR) are voltage- and glutamate-gated heteromeric ion channels 
      found at excitatory neuronal synapses, the functions of which are to mediate the 
      mechanisms of brain plasticity and, thereby, its higher order functions. In 
      addition to Glu, the activation of these heteromeric receptors requires Gly or 
      d-Ser as a coagonist. However, it is not fully known as to why coagonism is 
      required for the opening of NMDAR ion channels. We show herein that the ligand 
      binding domains (LBD) of the GluN1 and GluN2A subunits of the NMDAR 
      heterodimerize only when both coagonists, Glu and Gly/d-Ser, bind to their 
      respective sites on GluN2 and GluN1. In the agonist-free state, these domains 
      form homomeric interactions, which are disrupted by binding of their respective 
      agonists. Also, in a heteromer formed by the LBDs, GluN2A is more sensitized to 
      bind Glu, while the affinity of Gly for GluN1 remains unchanged. We thus provide 
      direct evidence to show that coagonism is necessary for heteromeric pairing of 
      LBDs, which is an essential step in forming functional ion channels in NMDARs.
FAU - Cheriyan, John
AU  - Cheriyan J
AD  - W. M. Keck Center for Transgene Research and the Department of Chemistry and 
      Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United 
      States.
FAU - Mezes, Christina
AU  - Mezes C
FAU - Zhou, Ning
AU  - Zhou N
FAU - Balsara, Rashna D
AU  - Balsara RD
FAU - Castellino, Francis J
AU  - Castellino FJ
LA  - eng
GR  - HL019982/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150108
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Ligands)
RN  - 0 (Protein Subunits)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Animals
MH  - Glutamic Acid/*metabolism
MH  - Glycine/*metabolism
MH  - Ion Channel Gating/drug effects
MH  - Ligands
MH  - Mice
MH  - Models, Molecular
MH  - N-Methylaspartate/pharmacology
MH  - *Protein Multimerization/drug effects
MH  - Protein Structure, Tertiary
MH  - Protein Subunits/metabolism
MH  - Rats
MH  - Receptors, N-Methyl-D-Aspartate/*agonists/*chemistry/metabolism
PMC - PMC4310633
EDAT- 2014/12/30 06:00
MHDA- 2015/04/15 06:00
PMCR- 2015/12/22
CRDT- 2014/12/30 06:00
PHST- 2014/12/30 06:00 [entrez]
PHST- 2014/12/30 06:00 [pubmed]
PHST- 2015/04/15 06:00 [medline]
PHST- 2015/12/22 00:00 [pmc-release]
AID - 10.1021/bi501437s [doi]
PST - ppublish
SO  - Biochemistry. 2015 Jan 27;54(3):787-94. doi: 10.1021/bi501437s. Epub 2015 Jan 8.