Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB phosphorylation in the rat brain.
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.
Toscano
Christopher D
CD
Department of Environmental Health Sciences, The Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, Room W2001, Baltimore, MD 21205, USA.
Hashemzadeh-Gargari
Hossein
H
McGlothan
Jennifer L
JL
Guilarte
Tomás R
TR
D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D007854:Lead / Q000633:toxicity*; D020263:Lead Poisoning, Nervous System / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D021122:Protein Subunits / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010880:Piperidines; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead; D016291:Dizocilpine Maleate; C010739:ifenprodil