News and Publications
Sando, R., Jiang, X., and Südhof, T.C. (2019) Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins. Science 363, pii: eaav7969.
Latrophilins are adhesion GPCRs that are essential for the formation of a subset of synapses. Sando et al. now show that they function by interacting with two ligands, but that their autoproteolysis via the GAIN domain is not required.
Wang, C.Y., Liu, Z., Ng, Y.H., and Südhof, T.C. (2020) A synaptic circuit required for acquisition but not recall of social transmission of food preference. Neuron 107, 144-157.
C1ql3 is a secreted ligand for the postsynaptic adhesion GPCR Bai3. Wang et al. show that presynaptic C1ql3 and its postsynaptic receptor Bai3 are necessary for formation of functional synaptic projections from the anterior olfactory nucleus to the olfactory bulb and that this projection is required for acquisition of social transmission of food preference memory in mice.
Luo, F., Sclip, A., Jiang, M., and Südhof, T.C. (2020) Neurexins Cluster Ca2+ Channels within presynaptic Active Zone. EMBO J. 39, e103208.
Luo et al. demonstrate that deletion of all neurexins from the calyx of Held synapse in the brainstem suppresses neurotransmitter release evoked by action potentials because the influx of calcium into the presynaptic terminal is impaired. The release machinery itself is intact, and the total amount of depolarization-evoked calcium influx into the nerve terminal is not decreased. Instead, the loss of neurexins suppresses neurotransmitter release because the calcium channels are more distant to the release sites, causing a spatial uncoupling of calcium influx and neurotransmitter release sites.
Patzke, C., Brockmann, M.M., Dai, J., Gan, K.J., Grauel, M.K., Fenske, P., Liu, Y., Acuna, C., Rosenmund, C., and Südhof, T.C. (2019) Neuromodulator Signaling Bidirectionally Controls Vesicle Numbers in Human Synapses. Cell 179, 498-513.
Synapsins are peripheral membrane proteins of synaptic vesicles that dissociate from the vesicles when their N-terminus is phosphorylated by CaM Kinase I or by protein kinase-A. Patzke et al. show that neuromodulators binding to presynaptic receptors control the number of synaptic vesicles in a nerve terminal by up- or down-regulating the N-terminal phosphorylation of synapsins. This represents a novel mechanism of neuromodulator signaling that operates in human and in mouse neurons to dynamically adjust neurotransmission.
Khajal, A.J., Sterky, F.H., Sclip, A., Schwenk, J., Brunger, A.T., Fakler, B., and Südhof, T.C. (2020) Deorphanizing FAM19A Proteins as Pan-Neurexin Ligands with an Unusual Biosynthetic Binding Mechanism. J. Cell Biol. 219, e202004164.
FAM19As are secreted cysteine-rich proteins that were thought to be cytokines owing to the primary structure. Khajal et al. discovered that FAM19A proteins bind to all neurexins via a covalent mechanism that involves formation of disulfide bonds by the FAM19A proteins and the Cysteine-loop domain of neurexins. Binding of FAM19A proteins to neurexins occurs during export in the secretory pathway of a neuron, and abolishes attachment of heparan sulfate modifications to neurexins via steric hindrance.