Association of PSD-95 with ErbB4 facilitates neuregulin signaling in cerebellar granule neurons in culture.
The growth factor neuregulin 1 (NRG) selectively induces an increase in the gamma-aminobutyric acid (GABA)(A) receptor beta2 subunit protein in rat cerebellar granule neurons in culture. We previously demonstrated that NRG acts by triggering ErbB4 receptor phosphorylation and subsequent signaling through the mitogen-activated kinase (MAPK), phosphatidyl inositol-3 kinase (PI-3K) and cyclin-dependent kinase 5 (cdk5) pathways. In this report we show that the scaffolding protein, PSD-95, plays a key role in mediating the effects of NRG and that reducing its level attenuates the NRG-induced increase in beta2 subunit expression. PSD-95 appears to facilitate the effects of NRG through its association with ErbB4, an interaction that is augmented by NRG-activated cdk signaling. Inhibition of cdk activity with roscovitine attenuates the association of PSD-95 with ErbB4. The effects of cdk5 are not blocked by U0126, an inhibitor of MAPK signaling, indicating that cdk5 functions independently of cross-talk with this pathway. These findings raise the possibility that NRG-induced activation of cdk5 works in part by recruiting PSD-95, a protein involved in regulating synaptic plasticity, to associate with ErbB4. This interaction may be a positive feedback loop that augments NRG signaling and its downstream effects on GABA(A) receptor beta2 subunit expression.
Xie
Fang
F
Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4965, USA.
Padival
Mallika
M
Siegel
Ruth E
RE
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004347:Drug Interactions; D066246:ErbB Receptors / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D020890:Neuregulin-1 / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010770:Phosphotransferases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
C492235:Cdk5r1 protein, rat; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020890:Neuregulin-1; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D010770:Phosphotransferases; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D051360:Cyclin-Dependent Kinase 5