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.

Figure caption: Rabies-virus tracing identifies changes in synaptic connections as a function of the expression of wild-type or mutant latrophilin-2 (Lphn2) or latrophilin-3 (Lphn3) in the hippocampus.

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.

Figure caption: Postsynaptic deletion of Bai3 in the olfactory bulb of Bai3 conditional KO mice has no detectable effect of basal olfaction, but essentially blocks acquisition of socially-transmitted food preference (STFP), a social form of appetitive memory.

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.

Figure caption: Deletion of neurexins impairs neurotransmitter release at an ambient 1 mM calcium concentration by suppressing the release probability, as indicated by the rise in paired-pulse ratio. The same suppression of release by the neurexin deletion is observed at a higher 2 mM ambient calcium concentration when the terminal contains the slow calcium buffer EGTA, which has no effect on release in wild-type synapses.

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.

Figure caption: Schematic illustrating the role of synapsin-1 phosphorylation in regulating vesicle numbers. Neuromodulators that increase cAMP levels cause a dissociation of vesicles from the vesicle cluster by catalyzing the phosphorylation of synapsins, whereas neuromodulators that decrease cAMP levels induce a recruitment of vesicles into the vesicle cluster by decreasing synapsin phosphorylation.

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.

Figure caption: Schematic of neurexin-1b (Nrxn1b) as a prototypical neurexin that does not contain a covalently attached FAM19A protein but is modified by a heparan sulfate (left), or that is complexed with a FAM19A protein and as a result is not modified by heparan sulfate (right).