Activity-Dependent IGF-1 Exocytosis Is Controlled by the Ca2+-Sensor Synaptotagmin-10

Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, 1050 Arastradero Rd., Palo Alto, California 94305, USA.
Cell (Impact Factor: 32.24). 04/2011; 145(2):300-11. DOI: 10.1016/j.cell.2011.03.034
Source: PubMed


Synaptotagmins Syt1, Syt2, Syt7, and Syt9 act as Ca(2+)-sensors for synaptic and neuroendocrine exocytosis, but the function of other synaptotagmins remains unknown. Here, we show that olfactory bulb neurons secrete IGF-1 by an activity-dependent pathway of exocytosis, and that Syt10 functions as the Ca(2+)-sensor that triggers IGF-1 exocytosis in these neurons. Deletion of Syt10 impaired activity-dependent IGF-1 secretion in olfactory bulb neurons, resulting in smaller neurons and an overall decrease in synapse numbers. Exogenous IGF-1 completely reversed the Syt10 knockout phenotype. Syt10 colocalized with IGF-1 in somatodendritic vesicles of olfactory bulb neurons, and Ca(2+)-binding to Syt10 caused these vesicles to undergo exocytosis, thereby secreting IGF-1. Thus, Syt10 controls a previously unrecognized pathway of Ca(2+)-dependent exocytosis that is spatially and temporally distinct from Ca(2+)-dependent synaptic vesicle exocytosis controlled by Syt1. Our findings thereby reveal that two different synaptotagmins can regulate functionally distinct Ca(2+)-dependent membrane fusion reactions in the same neuron.

37 Reads
  • Source
    • "Moreover, a range of synaptotagmin-family transcripts, which mediate different aspects of calciumdependent vesicle release, are selectively regulated in AGRP neurons by food deprivation (Figure 3E). For example, Syt5, Syt9, and Syt10 are upregulated in AGRP neurons from FD mice, and these gene products localize to peptidergic vesicles and regulate activity-dependent peptide release (Cao et al., 2011). GABA signaling is also important in AGRP neurons, and synaptic vesicle glycoprotein 2C (Sv2c, +5.4-fold, q = 5e −10 ), which regulates the readily releasable pool (Xu and Bajjalieh, 2001) is increased, as is Snap25 (+2.1-fold, p = 1.5e −6 ), a key SNARE complex component responsible for vesicle fusion. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular and cellular processes in neurons are critical for sensing and responding to energy deficit states, such as during weight-loss. AGRP neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific transcriptomics can be used to identify pathways that counteract weight-loss, and here we report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived young adult mice. For comparison, we also analyzed POMC neurons, an intermingled population that suppresses appetite and body weight. We find that AGRP neurons are considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion channels, neuropeptides, and receptors. Combined with methods to validate and manipulate these pathways, this resource greatly expands molecular insight into neuronal regulation of body weight, and may be useful for devising therapeutic strategies for obesity and eating disorders.
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.09800 · 9.32 Impact Factor
  • Source
    • ", and loss of these latter isoforms has not been associated with enhanced synaptic depression (Maximov and Sudhof, 2005; Pang et al., 2006; Sun et al., 2007; Xu et al., 2007; Dean et al., 2009; Liu et al., 2009; Cao et al., 2011; Dean et al., 2012a). These findings underscore both the specificity of the syt 7@BULLETCaM interaction, as well as the specific role played by syt 7 during synaptic depression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: eLife digest Neurons communicate with one another at junctions called synapses. The arrival of an electrical signal called an action potential at the first neuron triggers the release of chemicals called neurotransmitters into the synapse. These chemicals then diffuse across the gap between the neurons and bind to receptors on the second cell. The neurotransmitter molecules are stored in the first cell in packages known as vesicles, which release their contents by fusing with the cell membrane. Following a fusion event, neurons must replenish their vesicle stocks to ensure that they are ready for the arrival of the next action potential. This replenishment process is known to involve a calcium-dependent pathway and a calcium-independent pathway. A protein called calmodulin, that binds calcium ions, has an important role in the first of these pathways. Now, Liu et al. have shown that another protein, synaptotagmin 7, also has a key role in the replenishment of synaptic vesicles, possibly as a sensor for calcium ions. Moreover, Liu et al. found that synaptotagmin 7 and calmodulin bind to each other to form a complex, which suggests that the calcium-dependent replenishment pathway is regulated by this complex. The synaptotagmins are a family of 17 proteins, three of which are present in all animals. Two of these were known to have roles in synapses, but the role of the third—synaptotagmin 7—had been unclear. In addition to providing a more complete understanding of the replenishment of synaptic vesicles, the work of Liu et al. also supplies the final piece of the jigsaw regarding the role of the synaptotagmins that are present in all animals. DOI:
    eLife Sciences 02/2014; 3(3):e01524. DOI:10.7554/eLife.01524 · 9.32 Impact Factor
  • Source
    • "This is puzzling given the localization of Syt7 to secretory vesicles in nonneuronal cells (Chakrabarti et al., 2003; Fukuda et al., 2004; Schonn et al., 2008; Gustavsson et al., 2008, 2009). Second, whereas in all vesicular synaptotagmins tested up to date, the C2B domain Ca 2+ -binding sites are essential for Ca 2+ stimulation of exocytosis and the C2A domain Ca 2+ -binding sites only assist in Ca 2+ triggering of exocytosis (e.g., see Mackler et al., 2002; Nishiki and Augustine, 2004; Shin et al., 2009; Cao et al., 2011; Lee et al., 2013), in Syt7 "
    [Show abstract] [Hide abstract]
    ABSTRACT: During an action potential, Ca(2+) entering a presynaptic terminal triggers synaptic vesicle exocytosis and neurotransmitter release in less than a millisecond. How does Ca(2+) stimulate release so rapidly and precisely? Work over the last decades revealed that Ca(2+) binding to synaptotagmin triggers release by stimulating synaptotagmin binding to a core fusion machinery composed of SNARE and SM proteins that mediates membrane fusion during exocytosis. Complexin adaptor proteins assist synaptotagmin by activating and clamping this core fusion machinery. Synaptic vesicles containing synaptotagmin are positioned at the active zone, the site of vesicle fusion, by a protein complex containing RIM proteins. RIM proteins activate docking and priming of synaptic vesicles and simultaneously recruit Ca(2+) channels to active zones, thereby connecting in a single complex primed synaptic vesicles to Ca(2+) channels. This architecture allows direct flow of Ca(2+) ions from Ca(2+) channels to synaptotagmin, which then triggers fusion, thus mediating tight millisecond coupling of an action potential to neurotransmitter release.
    Neuron 10/2013; 80(3):675-90. DOI:10.1016/j.neuron.2013.10.022 · 15.05 Impact Factor
Show more