PMID- 12480136
OWN - NLM
STAT- MEDLINE
DCOM- 20030402
LR  - 20190901
IS  - 0165-3806 (Print)
IS  - 0165-3806 (Linking)
VI  - 139
IP  - 2
DP  - 2002 Dec 15
TI  - Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB 
      phosphorylation in the rat brain.
PG  - 217-26
AB  - In the present study we show that chronic exposure to low levels of lead (Pb(2+)) 
      during development alters the type of N-methyl-D-aspartate receptor (NMDAR) 
      expressed in the developing and young adult rat brain. Ifenprodil inhibition of 
      [3H]MK-801 binding to the NMDAR channel in cortical and hippocampal neuronal 
      membranes expressed high and low affinity components. Previous studies have shown 
      that the high affinity component is associated with NR1/NR2B receptor complexes 
      while the low affinity component is associated with the appearance and insertion 
      of the NR2A subunit to NMDAR complexes. Pb(2+)-exposed rats express a greater 
      number of [3H]MK-801 binding sites associated with the high affinity and low 
      affinity components of ifenprodil inhibition. Further, [3H]ifenprodil saturation 
      isotherms and Scatchard analysis in cortical and hippocampal membranes showed a 
      higher number of binding sites (B(max)) with no change in binding affinity (K(d)) 
      in Pb(2+)-exposed animals relative to controls. Quantitative [3H]MK-801 
      autoradiography in response to glutamate and glycine provided evidence that NMDAR 
      complexes in Pb(2+)-exposed rat brain were maximally activated in situ. Higher 
      levels of ifenprodil-sensitive binding sites and increased sensitivity to 
      agonists are properties characteristic of NR1/NR2B recombinant receptors. Thus, 
      our results strongly suggest that a greater proportion of the total number of 
      NMDAR are NR1/NR2B receptors in the Pb(2+)-exposed rat brain. This Pb(2+)-induced 
      change in NMDAR subtypes in the rat brain was associated with reduced CREB 
      phosphorylation in cortical and hippocampal nuclear extracts. These findings 
      demonstrate that chronic exposure to environmentally relevant levels of Pb(2+) 
      altered the subunit composition of NMDAR complexes with subsequent effects on 
      calcium-sensitive signaling pathways involved in CREB phosphorylation.
FAU - Toscano, Christopher D
AU  - Toscano CD
AD  - Department of Environmental Health Sciences, The Johns Hopkins University, 
      Bloomberg School of Public Health, 615 North Wolfe Street, Room W2001, Baltimore, 
      MD 21205, USA.
FAU - Hashemzadeh-Gargari, Hossein
AU  - Hashemzadeh-Gargari H
FAU - McGlothan, Jennifer L
AU  - McGlothan JL
FAU - Guilarte, Tomas R
AU  - Guilarte TR
LA  - eng
GR  - ES06189/ES/NIEHS NIH HHS/United States
GR  - ES07141/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Netherlands
TA  - Brain Res Dev Brain Res
JT  - Brain research. Developmental brain research
JID - 8908639
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (NR1 NMDA receptor)
RN  - 0 (NR2A NMDA receptor)
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (Piperidines)
RN  - 0 (Protein Subunits)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 2P299V784P (Lead)
RN  - 6LR8C1B66Q (Dizocilpine Maleate)
RN  - R8OE3P6O5S (ifenprodil)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Binding Sites/drug effects/physiology
MH  - Brain/*drug effects/growth & development/metabolism
MH  - Calcium Signaling/drug effects/physiology
MH  - Cell Differentiation/drug effects/physiology
MH  - Cyclic AMP Response Element-Binding Protein/*drug effects/metabolism
MH  - Dizocilpine Maleate/pharmacology
MH  - Environmental Exposure/*adverse effects
MH  - Female
MH  - Lead/*toxicity
MH  - Lead Poisoning, Nervous System/*metabolism/physiopathology
MH  - Male
MH  - Neurons/drug effects/metabolism
MH  - Phosphorylation/drug effects
MH  - Piperidines/pharmacology
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects
MH  - Protein Subunits/drug effects/metabolism
MH  - Rats
MH  - Rats, Long-Evans
MH  - Receptors, N-Methyl-D-Aspartate/*drug effects/metabolism
EDAT- 2002/12/14 04:00
MHDA- 2003/04/04 05:00
CRDT- 2002/12/14 04:00
PHST- 2002/12/14 04:00 [pubmed]
PHST- 2003/04/04 05:00 [medline]
PHST- 2002/12/14 04:00 [entrez]
AID - S0165380602005692 [pii]
AID - 10.1016/s0165-3806(02)00569-2 [doi]
PST - ppublish
SO  - Brain Res Dev Brain Res. 2002 Dec 15;139(2):217-26. doi: 
      10.1016/s0165-3806(02)00569-2.