Betz, Andrea

[["dc.bibliographiccitation.firstpage","123"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Neuron"],["dc.bibliographiccitation.lastpage","136"],["dc.bibliographiccitation.volume","21"],["dc.contributor.author","Betz, Andrea"],["dc.contributor.author","Ashery, Uri"],["dc.contributor.author","Rickmann, Michael"],["dc.contributor.author","Augustin, Iris"],["dc.contributor.author","Neher, Erwin"],["dc.contributor.author","Südhof, Thomas C."],["dc.contributor.author","Rettig, Jens"],["dc.contributor.author","Brose, Nils"],["dc.date.accessioned","2017-09-07T11:48:09Z"],["dc.date.available","2017-09-07T11:48:09Z"],["dc.date.issued","1998"],["dc.description.abstract","Munc13-1, a mammalian homolog of C. elegans unc-13p, is thought to be involved in the regulation of synaptic transmission. We now demonstrate that Munc13-1 is a presynaptic high-affinity phorbol ester and diacylglycerol receptor with ligand affinities similar to those of protein kinase C. Munc13-1 associates with the plasma membrane in response to phorbol ester binding and acts as a phorbol ester-dependent enhancer of transmitter release when overexpressed presynaptically in the Xenopus neuromuscular junction. These observations establish Munc13-1 as a novel presynaptic target of the diacylglycerol second messenger pathway that acts in parallel with protein kinase C to regulate neurotransmitter secretion."],["dc.identifier.doi","10.1016/S0896-6273(00)80520-6"],["dc.identifier.gro","3144539"],["dc.identifier.isi","000075061900012"],["dc.identifier.pmid","9697857"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2174"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Cell Press"],["dc.relation.eissn","1097-4199"],["dc.relation.issn","0896-6273"],["dc.title","Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","661"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Biochemical Society transactions"],["dc.bibliographiccitation.lastpage","666"],["dc.bibliographiccitation.volume","24"],["dc.contributor.author","Betz, A."],["dc.contributor.author","Telemenakis, I."],["dc.contributor.author","Hofmann, K."],["dc.contributor.author","Brose, N."],["dc.date.accessioned","2017-09-07T11:52:21Z"],["dc.date.available","2017-09-07T11:52:21Z"],["dc.date.issued","2015"],["dc.identifier.doi","10.1042/bst0240661"],["dc.identifier.gro","3144901"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2576"],["dc.language.iso","en"],["dc.notes.intern","Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","0300-5127"],["dc.title","Mammalian Unc-13 homologues as possible regulators of neurotransmitter release"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1200"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","The Journal of neuroscience"],["dc.bibliographiccitation.lastpage","1210"],["dc.bibliographiccitation.volume","27"],["dc.contributor.author","Basu, J."],["dc.contributor.author","Betz, A."],["dc.contributor.author","Brose, N."],["dc.contributor.author","Rosenmund, C."],["dc.date.accessioned","2017-09-07T11:49:51Z"],["dc.date.available","2017-09-07T11:49:51Z"],["dc.date.issued","2007"],["dc.description.abstract","Synapses need to encode a wide dynamic range of action potential frequencies. Essential vesicle priming proteins of the Munc13 (mammalian Unc13) family play an important role in adapting vesicle supply to variable demand and thus influence short-term plasticity characteristics and synaptic function. Structure-function analyses of Munc13s have identified a \"catalytic\" C-terminal domain and several N-terminal modulatory domains, including a diacylglycerol/phorbol ester [4 beta-phorbol-12, 13-dibutyrate (PDBu)] binding Cl domain. Although still allowing basal priming, a Munc13-1 C1 domain mutation (H567K) prevents PDBu induced potentiation of evoked transmitter release, leads to strong depression during trains of synaptic activity, and causes perinatal lethality in mice. To understand the mechanism of C1 domain-mediated modulation of Munc13 function, we examined how PDBu increases neurotransmitter release. Analyses of osmotically induced release as well as Ca2+ triggered and spontaneous release showed that PDBu increases the vesicular release rate without affecting the size of the readily releasable vesicle pool, linking C1 domain activation to a lowering of the energy barrier for vesicle fusion. PDBu binding-deficient mutant Munc13-1(H567K) synapses mirrored the vesicular release properties of PDBu-potentiated wild-type synapses, indicating that Munc13-1(H567K) is a gain-of-function mutant, which conformationally mimics the PDBu-activated state of Munc13-1. We propose a PKC analogous two-state model of regulation of Munc13s, in which the basal state of Munc13s is disinhibited by C1 domain activation into a state of facilitated vesicle release, regardless of whether the release is spontaneous or action potential triggered."],["dc.identifier.doi","10.1523/JNEUROSCI.4908-06.2007"],["dc.identifier.gro","3143542"],["dc.identifier.isi","000244069900028"],["dc.identifier.pmid","17267576"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1067"],["dc.notes.intern","WoS Import 2017-03-10 / Funder: NINDS NIH HHS [NS051262]"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0270-6474"],["dc.title","Munc13-1 C1 domain activation lowers the energy barrier for synaptic vesicle fusion"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","121"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cell"],["dc.bibliographiccitation.lastpage","133"],["dc.bibliographiccitation.volume","108"],["dc.contributor.author","Rhee, Jeong-Seop"],["dc.contributor.author","Betz, Andrea"],["dc.contributor.author","Pyott, S."],["dc.contributor.author","Reim, Kerstin"],["dc.contributor.author","Varoqueaux, Frederique"],["dc.contributor.author","Augustin, Iris"],["dc.contributor.author","Hesse, Dörte"],["dc.contributor.author","Südhof, Thomas C."],["dc.contributor.author","Takahashi, Masami"],["dc.contributor.author","Rosenmund, Christian"],["dc.contributor.author","Brose, Nils"],["dc.date.accessioned","2017-09-07T11:45:57Z"],["dc.date.available","2017-09-07T11:45:57Z"],["dc.date.issued","2002"],["dc.description.abstract","Munc13-1 is a presynaptic protein with an essential role in synaptic vesicle priming. It contains a diacylglycerol (DAG)/beta phorbol ester binding C-1 domain and is a potential target of the DAG second messenger pathway that may act in parallel with PKCs. Using genetically modified mice that express a DAG/beta phorbol ester binding-deficient Munc13-1(H567K) variant instead of the wild-type protein, we determined the relative contribution of PKCs and Munc13-1 to DAG/beta phorbol ester-dependent regulation of neurotransmitter release. We show that Munc13s are the main presynaptic DAG/beta phorbol ester receptors in hippocampal neurons. Modulation of Munc13-1 activity by second messengers via the DAG/beta phorbol ester binding C-1 domain is essential for use-dependent alterations of synaptic efficacy and survival."],["dc.identifier.doi","10.1016/S0092-8674(01)00635-3"],["dc.identifier.gro","3144226"],["dc.identifier.isi","000173280700013"],["dc.identifier.pmid","11792326"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1827"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0092-8674"],["dc.title","β Phorbol Ester- and Diacylglycerol-Induced Augmentation of Transmitter Release Is Mediated by Munc13s and Not by PKCs"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.volume","1763"],["dc.contributor.author","Dimova, K."],["dc.contributor.author","Kawabe, H."],["dc.contributor.author","Betz, A."],["dc.contributor.author","Brose, N."],["dc.contributor.author","Jahn, O."],["dc.date.accessioned","2017-09-07T11:52:24Z"],["dc.date.available","2017-09-07T11:52:24Z"],["dc.date.issued","2006"],["dc.description.abstract","Sensing of and response to transient increases in the residual presynaptic Ca2+ levels are important adaptive mechanisms that define the short-term plasticity characteristics of neurons. Due to their essential function in synaptic vesicle priming and in the modulation of synaptic strength, Munc13 proteins have emerged as key regulators of these adaptive mechanisms. Indeed, Munc13-1 and ubMunc13-2 contain a conserved calmodulin (CaM) binding site and the Ca2+-dependent interaction of these Munc 13 isoforms with CaM constitutes a molecular mechanism that transduces residual Ca2+ signaling to the synaptic exocytotic machinery. Here, we used Munc13-derived model peptides in photoaffinity labeling (PAL) experiments to demonstrate the stoichiometric and Ca2+-dependent CaM binding of the other members of the Munc13 family, bMunc13-2 and Munc13-3, via structurally distinct non-conserved binding sites. A PAL-based Ca2+ titration assay revealed that all Munc 13 isoforms can form a complex with CaM already at low Ca2+ concentrations just above resting levels, underscoring the Ca2+ sensor/effector function of this interaction in short-term synaptic plasticity phenomena. (c) 2006 Elsevier B.V. All rights reserved."],["dc.identifier.doi","10.1016/j.bbamcr.2006.09.017"],["dc.identifier.gro","3143593"],["dc.identifier.isi","000242892200014"],["dc.identifier.pmid","17049382"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1125"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Elsevier Science Bv"],["dc.publisher.place","Amsterdam"],["dc.relation.eventlocation","Ecole Superieure Biotechnol, Strasbourg, FRANCE"],["dc.relation.ispartof","Biochimica et Biophysica Acta (BBA) - Molecular Cell Research"],["dc.relation.issn","0167-4889"],["dc.title","Characterization of the Munc13-calmodulin interaction by photoaffinity labeling"],["dc.type","conference_paper"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","463"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Cell Metabolism"],["dc.bibliographiccitation.lastpage","468"],["dc.bibliographiccitation.volume","3"],["dc.contributor.author","Kang, L. J."],["dc.contributor.author","He, ZX"],["dc.contributor.author","Xu, P Y"],["dc.contributor.author","Fan, J. M."],["dc.contributor.author","Betz, Andrea"],["dc.contributor.author","Brose, Nils"],["dc.contributor.author","Xu, T"],["dc.date.accessioned","2017-09-07T11:52:41Z"],["dc.date.available","2017-09-07T11:52:41Z"],["dc.date.issued","2006"],["dc.description.abstract","Munc13-1 is a presynaptic protein that is essential for synaptic vesicle priming. Deletion of Munc13-1/unc13 causes total arrest of synaptic transmission due to a complete loss of fusion-competent synaptic vesicles. The requirement of Munc13-1 for large dense-core vesicles (LDCVs), however, has not been established. In the present study, we use Munc13-1 knockout (KO) and diacylglycerol (DAG) binding-deficient Munc13-1(H567K) mutant knockin (KI) mice to determine the role of Munc13-1 in the secretion of insulin-containing LDCVs from primary cultured pancreatic beta cells. We show that Munc13-1 is required for the sustained insulin release upon prolonged stimulation. The sustained release involves signaling of DAG second messenger, since it is also reduced in KI mice. Insulin secretion in response to glucose stimulation is characterized by a biphasic time course. Our data show that Munc13-1 plays an essential role in the development of the second phase of insulin secretion by priming insulin-containing LDCVs."],["dc.identifier.doi","10.1016/j.cmet.2006.04.012"],["dc.identifier.gro","3143682"],["dc.identifier.isi","000238199600010"],["dc.identifier.pmid","16697276"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1222"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Cell Press"],["dc.relation.issn","1550-4131"],["dc.title","Munc13-1 is required for the sustained release of insulin from pancreatic beta cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","328"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Current Opinion in Neurobiology"],["dc.bibliographiccitation.lastpage","340"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Brose, Nils"],["dc.contributor.author","Betz, Andrea"],["dc.contributor.author","Wegmeyer, Heike"],["dc.date.accessioned","2017-09-07T11:43:23Z"],["dc.date.available","2017-09-07T11:43:23Z"],["dc.date.issued","2004"],["dc.description.abstract","Diacylglycerol is an essential second messenger in mammalian cells. The most prominent intracellular targets of diacylglycerol and the functionally analogous phorbol esters belong to the protein kinase C family, but at least five alternative types of high affinity diacylglycerol/phorbol ester receptors are known: protein kinase D, diacylglycerol kinases alpha, beta, and gamma, RasGRPs, chimaerins, and Munc13s. These function independently of protein kinase C isozymes, and form a network of signaling pathways in the diacylglycerol second messenger system that regulates processes as diverse as gene transcription, lipid signaling, cytoskeletal dynamics, intracellular membrane trafficking, or neurotransmitter release."],["dc.identifier.doi","10.1016/j.conb.2004.05.006"],["dc.identifier.gro","3143981"],["dc.identifier.isi","000222538500009"],["dc.identifier.pmid","15194113"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1554"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Current Biology Ltd"],["dc.relation.issn","0959-4388"],["dc.title","Divergent and convergent signaling by the diacylglycerol second messenger pathway in mammals"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1421"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Diabetes"],["dc.bibliographiccitation.lastpage","1429"],["dc.bibliographiccitation.volume","55"],["dc.contributor.author","Kwan, E. P."],["dc.contributor.author","Xie, L"],["dc.contributor.author","Sheu, L."],["dc.contributor.author","Nolan, C. J."],["dc.contributor.author","Prentki, M."],["dc.contributor.author","Betz, Andrea"],["dc.contributor.author","Brose, Nils"],["dc.contributor.author","Gaisano, H. Y."],["dc.date.accessioned","2017-09-07T11:52:42Z"],["dc.date.available","2017-09-07T11:52:42Z"],["dc.date.issued","2006"],["dc.description.abstract","Munc13-1 is a diacylglycerol (DAG) receptor that is essential for synaptic vesicle priming. We recently showed that Munc13-1 is expressed in rodent and human islet beta-cells and that its levels are reduced in islets of type 2 diabetic humans and rat models, suggesting that Munc13-1 deficiency contributes to the abnormal insulin secretion in diabetes. To unequivocally demonstrate the role of Munc13-1 in insulin secretion, we studied heterozygous Munc13-1 knockout mice (+/-), which exhibited elevated glucose levels during intraperitoneal glucose tolerance tests with corresponding lower serum insulin levels. Munc13-1(+/-) mice exhibited normal insulin tolerance, indicating that a primary islet P-cell secretory defect is the major cause of their hyperglycemia. Consistently, glucose-stimulated insulin secretion was reduced 50% in isolated Munc13-1(+/-) islets and was only partially rescued by phorbol ester potentiation. The corresponding alterations were minor in mice expressing one allele of a Munc13-1 mutant variant, which does not bind DAG (H567K/+). Capacitance measurements of Munc13-1(+/-) and Munc13-1(H567k/+) islet P-cells revealed defects in granule priming, including the initial size and refilling of the releasable pools, which become accentuated by phorbol ester potentiation. We conclude that Munc13-1 plays an important role in glucose-stimulated insulin secretion and that Munc13-1 deficiency in the pancreatic islets as occurs in diabetes can reduce insulin secretion sufficient to cause abnormal glucose homeostasis."],["dc.identifier.doi","10.2337/db05-1263"],["dc.identifier.gro","3143692"],["dc.identifier.isi","000237303800030"],["dc.identifier.pmid","16644700"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1233"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Amer Diabetes Assoc"],["dc.relation.issn","0012-1797"],["dc.title","Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3586"],["dc.bibliographiccitation.issue","14"],["dc.bibliographiccitation.journal","EMBO Journal"],["dc.bibliographiccitation.lastpage","3596"],["dc.bibliographiccitation.volume","19"],["dc.contributor.author","Ashery, Uri"],["dc.contributor.author","Varoqueaux, Frederique"],["dc.contributor.author","Voets, T."],["dc.contributor.author","Betz, Andrea"],["dc.contributor.author","Koch, H."],["dc.contributor.author","Neher, Erwin"],["dc.contributor.author","Brose, Nils"],["dc.contributor.author","Rettig, Jens"],["dc.date.accessioned","2017-09-07T11:46:47Z"],["dc.date.available","2017-09-07T11:46:47Z"],["dc.date.issued","2000"],["dc.description.abstract","In chromaffin cells the number of large dense-core vesicles (LDCVs) which can be released by brief, intense stimuli represents only a small fraction of the 'morphologically docked' vesicles at the plasma membrane. Recently, it was shown that Munc13-1 is essential for a post-docking step of synaptic vesicle fusion, To investigate the role of Munc13-1 in LDCV exocytosis, we overexpressed Munc13-1 in chromaffin cells and stimulated secretion by flash photolysis of caged calcium. Both components of the exocytotic burst, which represent the fusion of release-competent vesicles, were increased by a factor of three. The sustained component, which represents vesicle maturation and subsequent fusion, was increased by the same factor. The response to a second flash, however, was greatly reduced, indicating a depletion of release-competent vesicles. Since there was no apparent change in the number of docked vesicles, we conclude that Munc13-1 acts as a priming factor by accelerating the rate constant of vesicle transfer from a pool of docked, but unprimed vesicles to a pool of release-competent, primed vesicles."],["dc.identifier.doi","10.1093/emboj/19.14.3586"],["dc.identifier.gro","3144373"],["dc.identifier.isi","000088447000008"],["dc.identifier.pmid","10899113"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1990"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0261-4189"],["dc.title","Munc13-1 acts as a priming factor for large dense-core vesicles in bovine chromaffin cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1594"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Cell"],["dc.bibliographiccitation.lastpage","1606"],["dc.bibliographiccitation.volume","149"],["dc.contributor.author","Riccomagno, Martin M."],["dc.contributor.author","Hurtado, Andrés"],["dc.contributor.author","Wang, HongBin"],["dc.contributor.author","Macopson, Joshua G. J."],["dc.contributor.author","Griner, Erin M."],["dc.contributor.author","Betz, Andrea"],["dc.contributor.author","Brose, Nils"],["dc.contributor.author","Kazanietz, Marcelo G."],["dc.contributor.author","Kolodkin, Alex L."],["dc.date.accessioned","2017-09-07T11:48:51Z"],["dc.date.available","2017-09-07T11:48:51Z"],["dc.date.issued","2012"],["dc.description.abstract","Axon pruning and synapse elimination promote neural connectivity and synaptic plasticity. Stereotyped pruning of axons that originate in the hippocampal dentate gyrus (DG) and extend along the infrapyramidal tract (IPT) occurs during postnatal murine development by neurite retraction and resembles axon repulsion. The chemorepellent Sema3F is required for IPT axon pruning, dendritic spine remodeling, and repulsion of DG axons. The signaling events that regulate IPT axon pruning are not known. We find that inhibition of the small G protein Rac1 by the Rac GTPase-activating protein (GAP) beta 2-Chimaerin (beta 2Chn) mediates Sema3F-dependent pruning. The Sema3F receptor neuropilin-2 selectively binds beta 2Chn, and ligand engagement activates this GAP to ultimately restrain Rac1-dependent effects on cytoskeletal reorganization. beta 2Chn is necessary for axon pruning both in vitro and in vivo, but it is dispensable for axon repulsion and spine remodeling. Therefore, a Npn2/beta 2Chn/Rac1 signaling axis distinguishes DG axon pruning from the effects of Sema3F on repulsion and dendritic spine remodeling."],["dc.identifier.doi","10.1016/j.cell.2012.05.018"],["dc.identifier.gro","3142515"],["dc.identifier.isi","000305753800023"],["dc.identifier.pmid","22726444"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/8875"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10 / Funder: National Ataxia Foundation; NIH [R01 CA74197, RO1 MH59199]"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0092-8674"],["dc.title","The RacGAP β2-Chimaerin Selectively Mediates Axonal Pruning in the Hippocampus"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]