The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses

Neuregulins regulate the expression of ligand- and voltage-gated channels i n neurons and skeletal muscle by the activation of their cognate tyrosine k inase receptors, ErbB 1-4. The subcellular distribution and mechanisms that regulate the localization of ErbB receptors are unknown. We have found tha t ErbB receptors are present in brain subcellular fractions enriched for po stsynaptic densities (PSD). The ErbB-4 receptor is unique among the ErbB pr oteins because its C-terminal tail (T-V-V) conforms to a sequence that bind s to a protein motif known as the PDZ domain, Using the yeast two-hybrid sy stem, we found that the C-terminal region of ErbB-4 interacts with the thre e related membrane-associated guanylate kinases (MAGUKs) PSD-95/SAP90. PSD- 93/chapsyn-110, and SAP 102, which harbor three PDZ domains, as well as wit h beta(2)-syntrophin, which has a single PDZ domain, As with N-methyl-D-asp artate (NMDA) receptors, ErbB-4 interacts with the first two PDZ domains of PSD-95, Using coimmunoprecipitation assays, we confirmed the direct intera ctions between ErbB-4 and PSD-95 in transfected heterologous cells, as well as in vivo, where both proteins are coimmunoprecipitated from brain lysate s. Moreover, evidence for colocalization of these proteins was also observe d by immunofluorescence in cultured hippocampal neurons. ErbB-4 colocalizes with PSD-95 and NMDA receptors at a subset of excitatory synapses apposed to synaptophysin-positive presynaptic terminals, The capacity of ErbB recep tors to interact with PDZ-domain proteins at cell junctions is conserved fr om invertebrates to mammals. As discussed, the interactions found between r eceptor tyrosine kinases and MAGUKs at neuronal synapses may have important implications for activity-dependent plasticity.