Mechanism of GABAB receptor-induced BDNF secretion and promotion of GABAA receptor membrane expression.
Recent studies have shown that GABA(B) receptors play more than a classical inhibitory role and can function as an important synaptic maturation signal early in life. In a previous study, we reported that GABA(B) receptor activation triggers secretion of brain-derived neurotrophic factor (BDNF) and promotes the functional maturation of GABAergic synapses in the developing rat hippocampus. To identify the signalling pathway linking GABA(B) receptor activation to BDNF secretion in these cells, we have now used the phosphorylated form of the cAMP response element-binding protein as a biological sensor for endogenous BDNF release. In the present study, we show that GABA(B) receptor-induced secretion of BDNF relies on the activation of phospholipase C, followed by the formation of diacylglycerol, activation of protein kinase C, and the opening of L-type voltage-dependent Ca(2+) channels. We further show that once released by GABA(B) receptor activation, BDNF increases the membrane expression of β(2/3) -containing GABA(A) receptors in neuronal cultures. These results reveal a novel function of GABA(B) receptors in regulating the expression of GABA(A) receptor through BDNF-tropomyosin-related kinase B receptor dependent signalling pathway.
INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 901, Marseille, France. kuczewski@inmed.univ-mrs.fr
Nicola
N
Kuczewski
Celine
C
Fuchs
Nadine
N
Ferrand
Jasmina N
JN
Jovanovic
Jean-Luc
JL
Gaiarsa
Christophe
C
Porcher
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics; D004075:Diglycerides / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018755:GABA Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D054799:Phospholipase C beta / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D018080:Receptors, GABA-B / Q000502:physiology*; D013570:Synaptic Membranes / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D004075:Diglycerides; D018755:GABA Agonists; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D011493:Protein Kinase C; D054799:Phospholipase C beta; D002118:Calcium