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The Journal of Neuroscience, April 15, 2003, 23(8):3164

Ligand-Dependent Recruitment of the ErbB4 Signaling Complex into Neuronal Lipid Rafts

Li Ma1, 2, *, Yang Z. Huang1, *, Graham M. Pitcher3, Juli G. Valtschanoff4, Ying H. Ma1, Lin Y. Feng2, Bai Lu5, Wen C. Xiong6, Michael W. Salter3, Richard J. Weinberg4, and Lin Mei1

1 Departments of Neurobiology, Pathology, and Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Civitan International Research Center, Birmingham, Alabama 35294, 2 Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, 3  Programmes in Brain and Behaviour and Cell Biology, Hospital for Sick Children, and Department of Physiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada, 4 Department of Cell and Developmental Biology and Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, 5 Unit on Synapse Development and Plasticity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, and 6 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294

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.

Key words: lipid rafts; ErbB4; NRG; PSD-95; postsynaptic density; long-term potentiation; synaptic plasticity

* L. M. and Y. Z. H. contributed equally to this work.

Copyright © 2003 Society for Neuroscience  0270-6474/03/2383164-12$05.00/0

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