Brain-derived neurotrophic factor exerts opposing effects on beta2-adrenergic receptor according to depolarization status of cerebellar neurons.
To investigate the molecular mechanisms underlying brain-derived neurotrophic factor (BDNF)-controlled synaptic plasticity, we studied beta2-adrenergic receptor (beta2-AR) expression in cultured cerebellar granule cells. We show that, depending on the state of depolarization, BDNF exerts opposite effects on beta2-AR expression. In neurons maintained in low K+ medium (5 mM K+) that will enter apoptosis, BDNF increases beta2-AR and beta2-AR transcripts. In contrast, in depolarized neurons (high K+ medium, 25 mM K+) BDNF represses beta2-AR expression. The use of reporter genes (driven by the beta2-AR promoter or restricted regulatory elements) revealed that BDNF exerts its opposite effects at the transcriptional level by recruiting a cyclic AMP response element (CRE) and the trans-acting factor CRE binding protein. These results provide the first evidence that a neurotrophin, e.g., BDNF, may exert an opposite effect on receptor expression and function (beta2-AR) according to the depolarization status of the neuron. Based on this finding, we propose that BDNF not only mediates neuronal survival, but is also involved in the modulation of the general sensitivity of the neuron to external signals, thus maintaining its optimal functional integration within the neuronal network.
Gaiddon
C
C
UMR 7519 CNRS, Institut de Physiologie et de Chimie Biologique, Université Louis Pasteur, Strasbourg, France.
Larmet
Y
Y
Trinh
E
E
Boutillier
A L
AL
Sommer
B
B
Loeffler
J P
JP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; D000242:Cyclic AMP; D007545:Isoproterenol; D011188:Potassium