Lead inhibition of NMDA channels in native and recombinant receptors.
NMDA channels are key targets for lead (Pb2+) neurotoxicity and Pb2+-induced inhibition of NMDA current is age- and subunit-dependent. In rat cerebellar granule cells maintained in high KCl, glycine affinity as well as sensitivity to ifenprodil change significantly with the days in vitro, indicating a reduction of NR2B subunit expression. Pb2+ blocked NMDA current with IC50 approximately 4 microM and this effect decreased significantly during the second week in vitro. In Xenopus laevis oocytes expressing recombinant NR1-NR2A, NR1-NR2B or NR1-NR2C receptors, Pb2+ inhibited glutamate-activated currents with IC50 of 3.3, 2.5 and 4.7 microM respectively. These data indicate that Pb2+ action is dependent on subunit composition and suggest that down-regulation of the NR2B subunit is correlated to a diminished sensitivity to Pb2+ inhibition.
Gavazzo
P
P
Istituto di Cibernetica e Biofisica, Consiglio Nazionale delle Ricerche, via De Marini 6, 16149 Genova, Italy.
Gazzoli
A
A
Mazzolini
M
M
Marchetti
C
C
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects* / Q000378:metabolism; D002525:Cerebellar Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004347:Drug Interactions / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005998:Glycine / Q000493:pharmacokinetics; D007854:Lead / Q000633:toxicity*; D020263:Lead Poisoning, Nervous System / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D018691:Excitatory Amino Acid Antagonists; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D007854:Lead; D011189:Potassium Chloride; C010739:ifenprodil; D005998:Glycine