Platelet-derived growth factor receptor is a novel modulator of type A gamma-aminobutyric acid-gated ion channels.
Platelet-derived growth factor (PDGF) and PDGF receptors (PDGFRs) are ubiquitously expressed in the mammalian central nervous system, where they exert trophic actions on both neuronal and glial cells. However, the acute actions of PDGF on synaptic transmission are unknown. We report a novel regulatory action of PDGF/PDGFR. Activation of PDGFRs inhibited the function of native type A gamma-aminobutyric acid (GABAA) receptors (GABAA-RS) in rat hippocampal CA1 pyramidal neurons and mouse brain membrane vesicles. The mechanism of this inhibition was studied with a panel of mutant PDGFRS-beta coexpressed with cloned human GABAA-Rs in Xenopus oocytes. These experiments revealed that phospholipase C-gamma is the protein that relays the inhibitory signal from PDGFRS to GABAA-Rs. Experiments with microinjected EGTA and inositol-1, 3, 4-triphosphate demonstrated that inhibition of GABAA-Rs depended on a phospholipase C-gamma-mediated increase in intracellular Ca(2+)-levels. The PDGFR-induced inhibitory effect was independent of the subunit composition of GABAA-RS. Moreover, GABAA-RS composed of alpha 1 beta 1 S409A subunits, which do not contain any known protein kinase C phosphorylation sites, were inhibited by PDGF to the same extent as wild-type GABAA-RS. Inhibitors of protein kinase C, CA2+/calmodulin-dependent protein kinase II, calcineurin, and tyrosine phosphatases did not affect the modulatory actions of PDGFR. In conclusion, our results suggest that PDGFRs exert potent modulatory actions on GABAA-R-dependent inhibitory synaptic transmission. These regulatory actions of PDGF could play important roles in the function of the mammalian central nervous system during physiological and pathophysiological conditions.
Valenzuela
C F
CF
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
Kazlauskas
A
A
Brozowski
S J
SJ
Weiner
J L
JL
Demali
K A
KA
McDonald
B J
BJ
Moss
S J
SJ
Dunwiddie
T V
TV
Harris
R A
RA
D000818:Animals; D001921:Brain / Q000502:physiology / Q000648:ultrastructure; D002118:Calcium / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000502:physiology / Q000648:ultrastructure; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology*; D018909:src Homology Domains / Q000502:physiology
D004791:Enzyme Inhibitors; D058787:GABA-A Receptor Antagonists; D007473:Ion Channels; D046911:Macromolecular Substances; D047428:Protein Kinase Inhibitors; D005680:gamma-Aminobutyric Acid; D017479:Receptors, Platelet-Derived Growth Factor; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium