Platelet-derived growth factor induces a long-term inhibition of N-methyl-D-aspartate receptor function.
Platelet-derived growth factor (PDGF) is a multifunctional protein that plays important roles in many tissues, including the mammalian central nervous system. PDGF and PDGF receptors (PDGFRs) are expressed in virtually every region of the central nervous system where they are involved in the development, survival, growth, and differentiation of both neuronal and glial cells. We now report that a brief activation of PDGFRs produced a long-lasting inhibition of N-methyl-D-aspartate (NMDA)-dependent excitatory postsynaptic currents in CA1 pyramidal neurons in rat hippocampal slices. PDGF also inhibited NMDA receptors (NMDA-Rs) in cultured hippocampal neurons by a mechanism that involves a decrease in single channel open probability. Non-NMDA receptor function was not affected by PDGF in hippocampal neurons. Experiments with mutant PDGFRs and chelation of intracellular Ca2+ in Xenopus oocytes indicate that this inhibition depends on a phospholipase C-gamma-induced elevation of intracellular Ca2+ levels. The PDGF-induced inhibition of NMDA-Rs is produced by a mechanism different than the well characterized phenomenon of Ca2+-dependent NMDA-R run down because the effect of PDGF was blocked by the phosphatase inhibitor, calyculin A, and was not affected by the microtubule polymerizing agent, phalloidin. Because elevations of PDGF levels are associated with neurological trauma or disease, we propose that PDGF can exert neuroprotective effects by inhibiting NMDA-R-dependent excitotoxicity.
Valenzuela
C F
CF
Department of Pharmacology and Program in Neuroscience, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Xiong
Z
Z
MacDonald
J F
JF
Weiner
J L
JL
Frazier
C J
CJ
Dunwiddie
T V
TV
Kazlauskas
A
A
Whiting
P J
PJ
Harris
R A
RA
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008387:Marine Toxins; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010080:Oxazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010590:Phalloidine / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014981:Xenopus
D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D010982:Platelet-Derived Growth Factor; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D010590:Phalloidine; C059041:calyculin A; D017479:Receptors, Platelet-Derived Growth Factor