Abstract
Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2 directly interacts with the PDZ domain-containing excitatory scaffolds, PSD-95 and Shank3. The interaction of Slitrk2 with PDZ proteins is mediated by the cytoplasmic COOH-terminal PDZ domain-binding motif (Ile-Ser-Glu-Leu), which is not found in other Slitrks. Mapping analyses further revealed that a single PDZ domain of Shank3 is responsible for binding to Slitrk2. Slitrk2 forms in vivo complexes with membrane-associated guanylate kinase (MAGUK) family proteins in addition to PSD-95 and Shank3. Intriguingly, in addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk2 is required for Slitrk2 promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Collectively, our data suggest a new molecular mechanism for conferring isoform-specific regulatory actions of the Slitrk family in orchestrating intracellular signal transduction pathways in postsynaptic neurons.
Highlights
Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs)
Recent efforts to identify a number of trans-synaptic adhesion molecules and investigate their synaptic roles has significantly contributed to our current understanding of how synapses are formed, refined, and eliminated[2]
PSD-95 and gephyrin contribute to the stabilization of interacting trans-membrane proteins (NMDA- and AMPA-type glutamate receptors, and various synaptic adhesion molecules) by suppressing their surface mobility or internalization[21]
Summary
Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). In addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk[2] is required for Slitrk[2] promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Synaptic cell-adhesion molecules have been recognized as key components that bidirectionally organize the transfer and processing of synaptic information[2] These proteins are thought to mediate the physical alignment of pre- and postsynaptic neurons, and to orchestrate multiple trans-cellular signaling cascades in both pre- and postsynaptic neurons, lending specific properties to synapse types. To explore the functions of Slitrk2-PDZ interactions, we performed various experiments in both cultured hippocampal neurons and hippocampal CA1 pyramidal neurons in vivo, revealing that PDZ proteins positively regulate excitatory synaptic targeting of Slitrk[2], as well as Slitrk2-mediated excitatory (but not inhibitory) synapse formation and transmission
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
