Transforming growth factor alpha attenuates the functional expression of AMPA receptors in cortical GABAergic neurons.
In the developing neocortex, brain-derived neurotrophic factor (BDNF) exerts a trophic activity to increase the expression and channel activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor subunits. Here, we demonstrate that the epidermal growth factor (EGF) receptor (ErbB1) ligands exert the opposite biological activity in cultured neocortical neurons. Subchronic stimulation of ErbB1 with transforming growth factor alpha (TGFalpha), EGF, or heparin-binding EGF (HB-EGF) down-regulated protein expression of the GluR1 AMPA receptor subunit in cultured neocortical neurons. In agreement, TGFalpha treatment decreased the Bmax of [3H] AMPA binding and GluR1 mRNA levels. Immunocytochemistry revealed that the decrease in GluR1 was most pronounced in multipolar GABAergic neurons. To examine the physiological consequences, we recorded AMPA-evoked currents as well as miniature excitatory postsynaptic currents in morphologically identified putative GABAergic neurons in culture. Subchronic TGFalpha treatment decreased AMPA-triggered currents as well as the amplitude and frequency of miniature excitatory postsynaptic currents. An ErbB1 tyrosine kinase inhibitor, PD153035, inhibited the TGFalpha effect. Moreover, TGFalpha counteracted the neurotrophic activity of BDNF on AMPA receptor expression. Co-application of TGFalpha with BDNF blocked the BDNF-triggered up-regulation of AMPA receptor expression and currents. These observations reveal a negative regulatory activity of the ErbB1 ligand, TGFalpha, which reduces the input sensitivity of cortical GABAergic neurons to attenuate their inhibitory function.
Namba
Hisaaki
H
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata 951-8585, Japan.
Nagano
Tadasato
T
Iwakura
Yuriko
Y
Xiong
Huabao
H
Jourdi
Hussam
H
Takei
Nobuyuki
N
Nawa
Hiroyuki
H
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism; D016895:Culture Media, Serum-Free; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000378:metabolism* / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D021122:Protein Subunits; D011799:Quinazolines; D018091:Receptors, AMPA; D016211:Transforming Growth Factor alpha; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005680:gamma-Aminobutyric Acid; C587885:Hbegf protein, rat; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline