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Synaptotagmin IV: a multifunctional regulator of peptidergic nerve terminals

Abstract

Many members of the synaptotagmin (Syt) protein family bind Ca2+ and trigger exocytosis, but some Syt proteins appear to have no Ca2+-dependent actions and their biological functions remain obscure. Syt IV is an activity-induced brain protein with no known Ca2+-dependent interactions and its subcellular localization and biological functions have sparked considerable controversy. We found Syt IV on both micro- and dense-core vesicles in posterior pituitary nerve terminals in mice. In terminals from Syt IV knockout mice compared with those from wild types, low Ca2+ entry triggered more exocytosis, high Ca2+ entry triggered less exocytosis and endocytosis was accelerated. In Syt IV knockouts, dense-core and microvesicle fusion was enhanced in cell-attached patches and dense-core vesicle fusion pores had conductances that were half as large as those in wild types. Given the neuroendocrine functions of the posterior pituitary, changes in Syt IV levels could be involved in endocrine transitions involving alterations in the release of the neuropeptides oxytocin and vasopressin.

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Figure 1: Syt IV expression.
Figure 2: Syt IV immunogold labeling in electron micrographs of posterior pituitary.
Figure 3: Voltage-dependent Ca2+ current in pituitary nerve terminals.
Figure 4: Ca2+-triggered capacitance changes.
Figure 5: Kinetics of endocytosis.
Figure 6: Single-vesicle capacitance steps.
Figure 7: Single-vesicle capacitance step sizes.
Figure 8: Depolarization with KCl-induced exocytosis in cell-attached patches.
Figure 9: Kiss-and-run fusion pores.

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Acknowledgements

We thank R. Jahn for monoclonal antibodies; R. Massey and B. August for assistance with electron microscopy; L. Bittova and J. Rehfuss for help with the western blots; and H. Herschman for providing the Syt4−/− mice. This work was supported by US National Institutes of Health grants to M.B.J. (NS30016 and NS44057) and E.R.C. (National Institute of General Medical Sciences grant GM56827 and National Institute of Mental Health grant MH61876) and an American Heart Association (0440168N) grant to E.R.C. C.D. was supported by a National Research Service Award. E.R.C. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Meyer B Jackson.

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Zhang, Z., Bhalla, A., Dean, C. et al. Synaptotagmin IV: a multifunctional regulator of peptidergic nerve terminals. Nat Neurosci 12, 163–171 (2009). https://doi.org/10.1038/nn.2252

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