Ligand-dependent recruitment of the ErbB4 signaling complex into neuronal lipid rafts.
Neuregulin (NRG) regulates synapse formation and synaptic plasticity, but little is known about the regulation of NRG signaling at synapses. Here we show that the NRG receptor ErbB4 was localized in anatomically defined postsynaptic densities in the brain. In cultured cortical neurons, ErbB4 was recruited to the neuronal lipid raft fraction after stimulation by NRG. Along with ErbB4, adaptor proteins Grb2 and Shc were translocated to lipid rafts by NRG stimulation. In transfected human embryonic kidney 293 cells, the partitioning of ErbB4 into a detergent-insoluble fraction that includes lipid rafts was increased by PSD-95 (postsynaptic density-95), through interaction of the ErbB4 C terminus with the PDZ [PSD-95/Discs large/zona occludens-1] domains of PSD-95. Disruption of lipid rafts inhibited NRG-induced activation of Erk and prevented NRG-induced blockade of induction of long-term potentiation at hippocampal CA1 synapses. Thus, our results indicate that NRG stimulation causes translocation of ErbB4 into lipid rafts and that lipid rafts are necessary for signaling by ErbB4.
Ma
Li
L
Department of Neurobiology, University of Alabama at Birmingham, Civitan International Research Center, Birmingham, Alabama 35294-0021, USA.
Huang
Yang Z
YZ
Pitcher
Graham M
GM
Valtschanoff
Juli G
JG
Ma
Ying H
YH
Feng
Lin Y
LY
Lu
Bai
B
Xiong
Wen C
WC
Salter
Michael W
MW
Weinberg
Richard J
RJ
Mei
Lin
L
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001923:Brain Chemistry; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D066246:ErbB Receptors / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D017774:Long-Term Potentiation / Q000502:physiology; D046911:Macromolecular Substances; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins; D016253:Microscopy, Immunoelectron; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000648:ultrastructure; D020880:Neuregulins / Q000378:metabolism / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D016012:Poisson Distribution; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495950:Grb2 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020880:Neuregulins; D011506:Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C033652:postsynaptic density proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D020928:Mitogen-Activated Protein Kinases