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• W2318691010 abstract "Editorial FociRepurposing molecular mechanisms of transmitter release: a new job for syndapin at the fusion pore. Focus on “Syndapin 3 modulates fusion pore expansion in mouse neuroendocrine chromaffin cells”Annie Quan, and Phillip J. RobinsonAnnie QuanCell Signalling Unit, Children's Medical Research Institute, The University of Sydney, Sydney, New South Wales, Australia, and Phillip J. RobinsonCell Signalling Unit, Children's Medical Research Institute, The University of Sydney, Sydney, New South Wales, AustraliaPublished Online:01 May 2014https://doi.org/10.1152/ajpcell.00079.2014This is the final version - click for previous versionMoreSectionsPDF (914 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat when a hormone- or neurotransmitter-filled vesicle reaches the plasma membrane and the stimulus conditions are right, the two membranes kiss. The kiss results in release of the vesicle contents by exocytosis by one of two modes, determined by a fusion pore. The fusion pore is a protein-lipid complex that creates a channel between the two membranes and is produced by soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) proteins, forcing the membranes to touch. These discoveries led to award of the 2013 Nobel Prize in Physiology or Medicine to Thomas Südhof, James Rothman, and Randy Schekman (7). The duration and outcome of the kiss, however, are controlled by the type and extent of stimulation. When the stimulus is low, the kiss can be as fleeting as milliseconds and involves a narrow fusion pore; if the stimulus is higher, it can last for many seconds through expansion of the fusion pore. After the fleeting kiss, the vesicle is quickly returned to the cell with much of its content intact; after the enduring kiss, the fusion pore expansion fully collapses the vesicle membrane into the plasma membrane, yielding a complete loss of its contents. The variability in fusion pore expansion allows signaling pathways to regulate which and how much hormone/transmitter is released. The decision to take one or another postkiss route involves dynamin.Exocytosis and endocytosis, crucial processes in neuroendocrine cells and neurons, have many mechanistic parallels (Fig. 1). Basal synaptic excitation in the sympathetic nervous system stimulates chromaffin cells of the adrenal medulla to release only modest levels of catecholamines. However, elevated sympathetic activity, such as during stress, greatly increases catecholamine release and also elicits peptide transmitter release from the same vesicle (3, 9). In this way, the same “large dense-core vesicle” can release one or more transmitters, at low or high concentrations (3). To achieve this, the higher-intensity stimulation causes fusion pore expansion. These vesicles are retrieved via endocytosis and recycled to maintain membrane homeostasis and secretion (2) (Fig. 1, top).Fig. 1.Repurposing of the calcineurin-dynamin-syndapin pathway. An influx of extracellular Ca2+ into the cytosol of neuroendocrine chromaffin cells (top) or presynaptic nerve terminals (bottom) upon depolarization triggers the docked vesicles to form a fusion pore from their SNARE proteins as a prelude to fusion with the plasma membrane, thereby releasing neurotransmitters and/or hormones by exocytosis. The same Ca2+ influx triggers retrieval of the empty vesicle from the plasma membrane by endocytosis. There are multiple modes of both exocytosis and endocytosis, based on kinetic parameters and molecular mechanisms. In neuroendocrine chromaffin cells, modes of exocytosis are shifted in an activity-dependent manner. Under basal stimulus, the fusion pore is narrow and favors lower catecholamine release; during intense stimulation, fusion pore expansion allows increased catecholamine release and releases peptide transmitters from the same vesicle by full fusion. The calcineurin-activated dynamin 1-syndapin 3 pathway is required for fusion pore expansion. It is not known if it is also required for bulk endocytosis (BE) in these cells. In presynaptic nerve terminals, after vesicle fusion, there are 3 main modes of endocytosis [clathrin-mediated endocytosis (CME), kiss-and-run, and activity-dependent bulk endocytosis (ADBE)], depending on the level of stimulus. The retrieved vesicles from each mode then are recycled into the larger pool and refilled with neurotransmitters for reuse. The calcineurin-activated dynamin 1-syndapin 1 protein complex regulates ADBE. How syndapin mediates ADBE is not understood.Download figureDownload PowerPointIn the central nervous system, nerve communication is also regulated by stimulus intensity, controlling the release of neurotransmitters, packaged inside synaptic vesicles (SVs), by exocytosis from presynaptic nerve terminals (Fig. 1, bottom). After vesicle fusion, SVs are retrieved to replenish the finite number of SVs available to maintain synaptic transmission. SV recycling is controlled by a series of orchestrated interactions between numerous regulatory proteins, depending on the level of neuronal activity (11). Vesicle retrieval in neuroendocrine cells and neurons is triggered by Ca2+ influx into the cell cytosol (1, 12). Depending on stimulus intensity, a variety of exo- and endocytic membrane trafficking modes, characterized by different chemical and kinetic parameters, have been observed (1, 11). Endocytosis involves single vesicles [kiss-and-run or clathrin-mediated endocytosis (CME)] or large membrane patches [bulk endocytosis (BE)]. The BE mechanism in neurons uses a distinct machinery that involves dynamin 1-syndapin interaction.Dynamin, a multi-isoform protein, is a GTPase responsible for scission of endocytic vesicles in CME in most cells (6). However, its activity-dependent phosphorylation has three other functions: activity-dependent BE (ADBE) in neurons (5), cytokinesis during mitosis (4), and fusion pore expansion in exocytosis from neuroendocrine cells (3). Thus a common mechanistic framework has been repurposed to regulate these functions in different cell types. In neurons, dephosphorylation of dynamin 1 by calcineurin, the Ca2+- and calmodulin-stimulated protein phosphatase, regulates ADBE (5). In mitosis, calcineurin-mediated dephosphorylation of dynamin 2 precedes cytokinesis (4). In chromaffin cells, calcineurin-mediated dephosphorylation of dynamin regulates fusion pore expansion to increase transmitter release (9).In this issue of American Journal of Physiology-Cell Physiology, Samasilp et al. (10) show a deeper parallel in this calcineurin-dynamin pathway. For bulk endocytosis in neurons, dynamin 1 dephosphorylation promotes a complex with syndapin 1 under conditions of intense neuronal stimulation (5). This signaling cassette is repurposed for fusion pore expansion in chromaffin cells, rather than BE (9). Samasilp et al. report that syndapin 3, rather than syndapin 1 or 2, mediates this process. Syndapin is a member of the Fes-CIP4 homology Bin-amphiphysin-Rvs161/167 (F-BAR) domain family of proteins that regulate a number of cellular processes (8). The NH2-terminal F-BAR domain confers the ability to sense membrane curvature and shape the membrane. The COOH-terminal Src homology 3 (SH3) domain mediates the connection to dynamin but also strongly interacts with neural Wiskott-Aldrich syndrome protein (N-WASP) for a role in actin dynamics. How syndapin operates mechanistically is more elusive. Some previous studies have intertwined the roles of the three isoforms (8); therefore, the isoform-specific functions of syndapin in cells are not at all clear. Thus, syndapin isoform selectivity could be a key regulator of protein function in different cells.Against this background, the observations of Samasilp et al. (10) are significant, because their work elucidates a clear physiological role for syndapin 3 in fusion pore expansion in chromaffin cells. They examined expression of syndapin 1, 2, and 3 in adrenal medullary tissue and found that syndapin 3 and 2 were the main isoforms expressed. However, in chromaffin cells, after overexpression of mutants in the SH3 domain of each syndapin isoform that block binding to the dynamin 1 tail, only overexpression of mutants in the SH3 domain of syndapin 3 reduced catecholamine quantal size, indicative of reduced fusion pore expansion. This effect was specific, as the mutant did not alter initial pore opening, Ca2+ current, or spike frequency, on the basis of electrochemical amperometry measurements. Definitive evidence that this role is strictly mediated by dynamin, rather than other syndapin SH3 domain partners, is still lacking.Repurposing of specific proteins for different biological functions is reasonably common in biology, but repurposing of larger signaling pathways, such as calcineurin-dynamin-syndapin, is more unusual. More questions are raised, such as whether this signaling cassette plays a role in BE in chromaffin cells (2). Conversely, is the signaling cassette involved in switching modes of transmitter release from SVs in neurons? These two scenarios would suggest multiple cellular events regulated by higher-intensity stimulation. Syndapin has emerged as a key protein in multiple cellular processes, although there is a long road ahead for a more complete understanding of its mechanisms of action in these roles. The main question becomes how syndapin regulates fusion pore expansion. Deciphering more of its molecular mechanism of action in different cellular processes will be key. Isoform selectivity within a larger molecular signaling cassette may identify new therapeutic strategies for modulating the stress responses in the body to restore homeostasis after injury or inflammation or to target synaptic transmission in neurons.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSA.Q. and P.J.R. prepared the figure; A.Q. and P.J.R. drafted the manuscript; A.Q. and P.J.R. edited and revised the manuscript; A.Q. and P.J.R. approved the final version of the manuscript.REFERENCES1. Artalejo CR, Elhamdani A, Palfrey HC. Sustained stimulation shifts the mechanism of endocytosis from dynamin-1-dependent rapid endocytosis to clathrin- and dynamin-2-mediated slow endocytosis in chromaffin cells. Proc Natl Acad Sci USA 99: 6358–6363, 2002.Crossref | PubMed | ISI | Google Scholar2. Cardenas AM, Marengo FD. Rapid endocytosis and vesicle recycling in neuroendocrine cells. Cell Mol Neurobiol 30: 1365–1370, 2010.Crossref | PubMed | ISI | Google Scholar3. Chan SA, Doreian B, Smith C. Dynamin and myosin regulate differential exocytosis from mouse adrenal chromaffin cells. Cell Mol Neurobiol 30: 1351–1357, 2010.Crossref | PubMed | ISI | Google Scholar4. Chircop M, Sarcevic B, Larsen MR, Malladi CS, Chau N, Zavortink M, Smith CM, Quan A, Anggono V, Hains PG, Graham ME, Robinson PJ. Phosphorylation of dynamin II at serine-764 is associated with cytokinesis. Biochim Biophys Acta 1813: 1689–1699, 2011.Crossref | PubMed | ISI | Google Scholar5. Clayton EL, Cousin MA. The molecular physiology of activity-dependent bulk endocytosis of synaptic vesicles. J Neurochem 111: 901–914, 2009.Crossref | PubMed | ISI | Google Scholar6. Ferguson SM, De Camilli P. Dynamin, a membrane-remodelling GTPase. Nat Rev Mol Cell Biol 11: 75–88, 2012.Crossref | ISI | Google Scholar7. Mellman I, Emr SD. A Nobel Prize for membrane traffic: vesicles find their journey's end. J Cell Biol 203: 559–561, 2013.Crossref | PubMed | ISI | Google Scholar8. Quan A, Robinson PJ. Syndapin, a membrane remodelling and endocytic F-BAR protein. FEBS J 280: 5198–5212, 2013.Crossref | PubMed | ISI | Google Scholar9. Samasilp P, Chan SA, Smith C. Activity-dependent fusion pore expansion regulated by a calcineurin-dependent dynamin-syndapin pathway in mouse adrenal chromaffin cells. J Neurosci 32: 10438–10447, 2012.Crossref | PubMed | ISI | Google Scholar10. Samasilp P, Lopin K, Chan SA, Ramachandran R, Smith C. Syndapin 3 modulates fusion pore expansion in mouse neuroendocrine chromaffin cells. Am J Physiol Cell Physiol (February 5, 2014). doi:10.1152/ajpcell.00291.2013.Link | ISI | Google Scholar11. Schweizer FE, Ryan TA. The synaptic vesicle: cycle of exocytosis and endocytosis. Curr Opin Neurobiol 16: 298–304, 2006.Crossref | PubMed | ISI | Google Scholar12. Sudhof TC. Calcium control of neurotransmitter release. Cold Spring Harb Perspect Biol 4: a011353, 2012.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: P. J. Robinson, Locked Bag 23, Wentworthville, Sydney, NSW 2145, Australia (e-mail: [email protected]org.au). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByThe Calcineurin-Binding, Activity-Dependent Splice Variant Dynamin1xb Is Highly Enriched in Synapses in Various Regions of the Central Nervous System25 July 2017 | Frontiers in Molecular Neuroscience, Vol. 10Small molecules demonstrate the role of dynamin as a bi-directional regulator of the exocytosis fusion pore and vesicle release5 May 2015 | Molecular Psychiatry, Vol. 20, No. 7Syndapin 3 modulates fusion pore expansion in mouse neuroendocrine chromaffin cellsPrattana Samasilp, Kyle Lopin, Shyue-An Chan, Rajesh Ramachandran, and Corey Smith1 May 2014 | American Journal of Physiology-Cell Physiology, Vol. 306, No. 9 More from this issue > Volume 306Issue 9May 2014Pages C792-C793 Copyright & PermissionsCopyright © 2014 the American Physiological Societyhttps://doi.org/10.1152/ajpcell.00079.2014PubMed24647543History Published online 1 May 2014 Published in print 1 May 2014 Metrics" @default.
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