Brandenburg, Sören

[["dc.bibliographiccitation.journal","Circulation Research"],["dc.contributor.author","Berisha, Filip"],["dc.contributor.author","Götz, Konrad"],["dc.contributor.author","Wegener, Jörg W."],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Subramanian, Hariharan"],["dc.contributor.author","Molina, Cristina E."],["dc.contributor.author","Rueffer, Andre"],["dc.contributor.author","Petersen, Johannes"],["dc.contributor.author","Bernhardt, Alexander"],["dc.contributor.author","Nikolaev, Viacheslav O."],["dc.date.accessioned","2021-06-01T10:47:48Z"],["dc.date.available","2021-06-01T10:47:48Z"],["dc.date.issued","2021"],["dc.description.abstract","Rationale: 3',5'-cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger which, upon β-adrenergic receptor (β-AR) stimulation, acts in microdomains to regulate cardiac excitation-contraction coupling by activating phosphorylation of calcium handling proteins. One crucial microdomain is in vicinity of the cardiac ryanodine receptor type 2 (RyR2) which is associated with arrhythmogenic diastolic calcium leak from the sarcoplasmic reticulum (SR) often occurring in heart failure. Objective: We sought to establish a real time live cell imaging approach capable of directly visualizing cAMP in the vicinity of mouse and human RyR2 and to analyze its pathological changes in failing cardiomyocytes under β-AR stimulation. Methods and Results: We generated a novel targeted fluorescent biosensor Epac1-JNC for RyR2-associated cAMP and expressed it in transgenic mouse hearts as well in human ventricular myocytes using adenoviral gene transfer. In healthy cardiomyocytes, β 1 -AR but not β 2 -AR stimulation strongly increased local RyR2-associated cAMP levels. However, already in cardiac hypertrophy induced by aortic banding, there was a marked subcellular redistribution of phosphodiesterases (PDEs) 2, 3 and 4, which included a dramatic loss of the local pool of PDE4. This was also accompanied by measurableβ2-AR/AMP signals in the vicinity of RyR2 in failing mouse and human myocytes, increased β2-AR-dependent RyR2 phosphorylation, SR calcium leak and arrhythmia susceptibility. Conclusions: Our new imaging approach could visualize cAMP levels in the direct vicinity of cardiac RyR2. Unexpectedly, in mouse and human failing myocytes, it could uncover functionally relevant local arrhythmogenic β2-AR/cAMP signals which might be an interesting antiarrhythmic target for heart failure."],["dc.identifier.doi","10.1161/CIRCRESAHA.120.318234"],["dc.identifier.pmid","33902292"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85724"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/393"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation.eissn","1524-4571"],["dc.relation.issn","0009-7330"],["dc.relation.workinggroup","RG Brandenburg"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Lehnart (Cellular Biophysics and Translational Cardiology Section)"],["dc.relation.workinggroup","RG Nikolaev (Cardiovascular Research Center)"],["dc.title","cAMP Imaging at Ryanodine Receptors Reveals β2-Adrenoceptor Driven Arrhythmias"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Weninger, Gunnar"],["dc.contributor.author","Pochechueva, Tatiana"],["dc.contributor.author","El Chami, Dana"],["dc.contributor.author","Luo, Xiaojing"],["dc.contributor.author","Kohl, Tobias"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Guan, Kaomei"],["dc.contributor.author","Lenz, Christof"],["dc.contributor.author","Lehnart, Stephan Elmar"],["dc.date.accessioned","2022-07-01T07:34:53Z"],["dc.date.available","2022-07-01T07:34:53Z"],["dc.date.issued","2022"],["dc.description.abstract","Calpains are calcium-activated neutral proteases involved in the regulation of key signaling pathways. Junctophilin-2 (JP2) is a Calpain-specific proteolytic target and essential structural protein inside Ca 2+ release units required for excitation-contraction coupling in cardiomyocytes. While downregulation of JP2 by Calpain cleavage in heart failure has been reported, the precise molecular identity of the Calpain cleavage sites and the (patho-)physiological roles of the JP2 proteolytic products remain controversial. We systematically analyzed the JP2 cleavage fragments as function of Calpain-1 versus Calpain-2 proteolytic activities, revealing that both Calpain isoforms preferentially cleave mouse JP2 at R565, but subsequently at three additional secondary Calpain cleavage sites. Moreover, we identified the Calpain-specific primary cleavage products for the first time in human iPSC-derived cardiomyocytes. Knockout of RyR2 in hiPSC-cardiomyocytes destabilized JP2 resulting in an increase of the Calpain-specific cleavage fragments. The primary N-terminal cleavage product NT 1 accumulated in the nucleus of mouse and human cardiomyocytes in a Ca 2+ -dependent manner, closely associated with euchromatic chromosomal regions, where NT 1 is proposed to function as a cardio-protective transcriptional regulator in heart failure. Taken together, our data suggest that stabilizing NT 1 by preventing secondary cleavage events by Calpain and other proteases could be an important therapeutic target for future studies."],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship"," Deutsches Zentrum für Herz-Kreislaufforschung http://dx.doi.org/10.13039/100010447"],["dc.description.sponsorship","Herzzentrum Göttingen"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.1038/s41598-022-14320-9"],["dc.identifier.pii","14320"],["dc.identifier.pmid","35725601"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/112032"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/179"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/508"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/435"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-581"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","SFB 1190 | P03: Erhaltung und funktionelle Kopplung von ER-Kontakten mit der Plasmamembran"],["dc.relation","SFB 1190 | Z02: Massenspektrometrie-basierte Proteomanalyse"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion"],["dc.relation.eissn","2045-2322"],["dc.relation.workinggroup","RG Lehnart (Cellular Biophysics and Translational Cardiology Section)"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Calpain cleavage of Junctophilin-2 generates a spectrum of calcium-dependent cleavage products and DNA-rich NT1-fragment domains in cardiomyocytes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","681"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","693"],["dc.bibliographiccitation.volume","140"],["dc.contributor.author","Alsina, Katherina M."],["dc.contributor.author","Hulsurkar, Mohit"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Kownatzki-Danger, Daniel"],["dc.contributor.author","Lenz, Christof"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Abu-Taha, Issam"],["dc.contributor.author","Kamler, Markus"],["dc.contributor.author","Chiang, David Y."],["dc.contributor.author","Lahiri, Satadru K."],["dc.contributor.author","Reynolds, Julia O."],["dc.contributor.author","Quick, Ann P."],["dc.contributor.author","Scott, Larry"],["dc.contributor.author","Word, Tarah A."],["dc.contributor.author","Gelves, Maria D."],["dc.contributor.author","Heck, Albert J.R."],["dc.contributor.author","Li, Na"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Lehnart, Stephan E."],["dc.contributor.author","Wehrens, Xander H.T."],["dc.date.accessioned","2020-12-10T18:38:03Z"],["dc.date.available","2020-12-10T18:38:03Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1161/CIRCULATIONAHA.119.039642"],["dc.identifier.pmid","31185731"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77173"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/203"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/133"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","SFB 1190 | P03: Erhaltung und funktionelle Kopplung von ER-Kontakten mit der Plasmamembran"],["dc.relation.workinggroup","RG Lehnart"],["dc.relation.workinggroup","RG Brandenburg"],["dc.relation.workinggroup","RG Lenz"],["dc.title","Loss of Protein Phosphatase 1 Regulatory Subunit PPP1R3A Promotes Atrial Fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Circulation Research"],["dc.bibliographiccitation.volume","128"],["dc.contributor.author","Peper, Jonas"],["dc.contributor.author","Kownatzki-Danger, Daniel"],["dc.contributor.author","Weninger, Gunnar"],["dc.contributor.author","Seibertz, Fitzwilliam"],["dc.contributor.author","Pronto, Julius Ryan D."],["dc.contributor.author","Sutanto, Henry"],["dc.contributor.author","Pacheu-Grau, David"],["dc.contributor.author","Hindmarsh, Robin"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Lehnart, Stephan E."],["dc.date.accessioned","2021-06-01T09:42:10Z"],["dc.date.available","2021-06-01T09:42:10Z"],["dc.date.issued","2021"],["dc.description.abstract","Rationale: CAV3 (caveolin3) variants associated with arrhythmogenic cardiomyopathy and muscular dystrophy can disrupt post-Golgi surface trafficking. As CAV1 (caveolin1) was recently identified in cardiomyocytes, we hypothesize that conserved isoform-specific protein/protein interactions orchestrate unique cardiomyocyte microdomain functions. To analyze the CAV1 versus CAV3 interactome, we employed unbiased live-cell proximity proteomic, isoform-specific affinity, and complexome profiling mass spectrometry techniques. We demonstrate the physiological relevance and loss-of-function mechanism of a novel CAV3 interactor in gene-edited human induced pluripotent stem cell cardiomyocytes. Objective: To identify differential CAV1 versus CAV3 protein interactions and to define the molecular basis of cardiac CAV3 loss-of-function. Methods and Results: Combining stable isotope labeling with proximity proteomics, we applied mass spectrometry to screen for putative CAV3 interactors in living cardiomyocytes. Isoform-specific affinity proteomic and co-immunoprecipitation experiments confirmed the monocarboxylate transporter McT1 (monocarboxylate transporter type 1) versus aquaporin1, respectively, as CAV3 or CAV1 specific interactors in cardiomyocytes. Superresolution stimulated emission depletion microscopy showed distinct CAV1 versus CAV3 cluster distributions in cardiomyocyte transverse tubules. CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9 nuclease)-mediated CAV3 knockout uncovered a stabilizing role for McT1 surface expression, proton-coupled lactate shuttling, increased late Na + currents, and early afterdepolarizations in human induced pluripotent stem cell-derived cardiomyocytes. Complexome profiling confirmed that McT1 and the Na,K-ATPase form labile protein assemblies with the multimeric CAV3 complex. Conclusions: Combining the strengths of proximity and affinity proteomics, we identified isoform-specific CAV1 versus CAV3 binding partners in cardiomyocytes. McT1 represents a novel class of metabolically relevant CAV3-specific interactors close to mitochondria in cardiomyocyte transverse tubules. CAV3 knockout uncovered a previously unknown role for functional stabilization of McT1 in the surface membrane of human cardiomyocytes. Strikingly, CAV3 deficient cardiomyocytes exhibit action potential prolongation and instability, reproducing human reentry arrhythmias in silico. Given that lactate is a major substrate for stress adaption both in the healthy and the diseased human heart, future studies of conserved McT1/CAV3 interactions may provide rationales to target this muscle-specific assembly function therapeutically."],["dc.identifier.doi","10.1161/CIRCRESAHA.119.316547"],["dc.identifier.pmid","33486968"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85167"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/216"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/383"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/135"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A06: Molekulare Grundlagen mitochondrialer Kardiomyopathien"],["dc.relation","SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation","SFB 1002 | D02: Neue Mechanismen der genomischen Instabilität bei Herzinsuffizienz"],["dc.relation","SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle"],["dc.relation","SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse"],["dc.relation","SFB 1002 | A13: Bedeutung einer gestörten zytosolischen Calciumpufferung bei der atrialen Arrhythmogenese bei Patienten mit Herzinsuffizienz (HF)"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation.eissn","1524-4571"],["dc.relation.issn","0009-7330"],["dc.relation.workinggroup","RG Hasenfuß"],["dc.relation.workinggroup","RG Lehnart"],["dc.relation.workinggroup","RG Rehling (Mitochondrial Protein Biogenesis)"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.relation.workinggroup","RG Brandenburg"],["dc.relation.workinggroup","RG Cyganek (Stem Cell Unit)"],["dc.relation.workinggroup","RG Lenz"],["dc.relation.workinggroup","RG Wollnik"],["dc.relation.workinggroup","RG Urlaub (Bioanalytische Massenspektrometrie)"],["dc.title","Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e51823"],["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.issue","92"],["dc.bibliographiccitation.journal","Journal of Visualized Experiments"],["dc.bibliographiccitation.lastpage","19"],["dc.contributor.author","Wagner, Eva"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Kohl, Tobias"],["dc.contributor.author","Lehnart, Stephan Elmar"],["dc.date.accessioned","2018-05-07T12:58:36Z"],["dc.date.available","2018-05-07T12:58:36Z"],["dc.date.issued","2014"],["dc.description.abstract","In cardiac myocytes a complex network of membrane tubules--the transverse-axial tubule system (TATS)--controls deep intracellular signaling functions. While the outer surface membrane and associated TATS membrane components appear to be continuous, there are substantial differences in lipid and protein content. In ventricular myocytes (VMs), certain TATS components are highly abundant contributing to rectilinear tubule networks and regular branching 3D architectures. It is thought that peripheral TATS components propagate action potentials from the cell surface to thousands of remote intracellular sarcoendoplasmic reticulum (SER) membrane contact domains, thereby activating intracellular Ca(2+) release units (CRUs). In contrast to VMs, the organization and functional role of TATS membranes in atrial myocytes (AMs) is significantly different and much less understood. Taken together, quantitative structural characterization of TATS membrane networks in healthy and diseased myocytes is an essential prerequisite towards better understanding of functional plasticity and pathophysiological reorganization. Here, we present a strategic combination of protocols for direct quantitative analysis of TATS membrane networks in living VMs and AMs. For this, we accompany primary cell isolations of mouse VMs and/or AMs with critical quality control steps and direct membrane staining protocols for fluorescence imaging of TATS membranes. Using an optimized workflow for confocal or superresolution TATS image processing, binarized and skeletonized data are generated for quantitative analysis of the TATS network and its components. Unlike previously published indirect regional aggregate image analysis strategies, our protocols enable direct characterization of specific components and derive complex physiological properties of TATS membrane networks in living myocytes with high throughput and open access software tools. In summary, the combined protocol strategy can be readily applied for quantitative TATS network studies during physiological myocyte adaptation or disease changes, comparison of different cardiac or skeletal muscle cell types, phenotyping of transgenic models, and pharmacological or therapeutic interventions."],["dc.identifier.doi","10.3791/51823"],["dc.identifier.pmid","25350293"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/14630"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/69"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A05: Molekulares Imaging von kardialen Calcium-Freisetzungsdomänen"],["dc.relation","SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion"],["dc.relation.doi","10.3791/51823"],["dc.relation.eissn","1940-087X"],["dc.relation.issn","1940-087X"],["dc.relation.workinggroup","RG Brandenburg"],["dc.relation.workinggroup","RG Lehnart (Cellular Biophysics and Translational Cardiology Section)"],["dc.title","Analysis of tubular membrane networks in cardiac myocytes from atria and ventricles"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","15"],["dc.bibliographiccitation.volume","173"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Drews, Lena"],["dc.contributor.author","Schönberger, Hanne-Lea"],["dc.contributor.author","Jacob, Christoph F."],["dc.contributor.author","Paulke, Nora Josefine"],["dc.contributor.author","Beuthner, Bo E."],["dc.contributor.author","Topci, Rodi"],["dc.contributor.author","Kohl, Tobias"],["dc.contributor.author","Neuenroth, Lisa"],["dc.contributor.author","Kutschka, Ingo"],["dc.contributor.author","Lehnart, Stephan E."],["dc.date.accessioned","2022-10-04T10:21:12Z"],["dc.date.available","2022-10-04T10:21:12Z"],["dc.date.issued","2022"],["dc.identifier.doi","10.1016/j.yjmcc.2022.08.363"],["dc.identifier.pii","S0022282822005193"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/114349"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-600"],["dc.relation.issn","0022-2828"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","1227"],["dc.bibliographiccitation.journal","Frontiers in Physiology"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Pawlowitz, Jan"],["dc.contributor.author","Lehnart, Stephan Elmar"],["dc.contributor.author","Fakuade, Funsho E."],["dc.contributor.author","Kownatzki-Danger, Daniel"],["dc.contributor.author","Kohl, Tobias"],["dc.contributor.author","Mitronova, Gyuzel Y."],["dc.contributor.author","Scardigli, Marina"],["dc.contributor.author","Neef, Jakob"],["dc.contributor.author","Schmidt, Constanze"],["dc.contributor.author","Wiedmann, Felix"],["dc.contributor.author","Pavone, Francesco S."],["dc.contributor.author","Sacconi, Leonardo"],["dc.contributor.author","Kutschka, Ingo"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Moser, Tobias"],["dc.contributor.author","Voigt, Niels"],["dc.date.accessioned","2022-05-13T09:20:22Z"],["dc.date.available","2022-05-13T09:20:22Z"],["dc.date.issued","2018-07-13"],["dc.description.abstract","Rationale: Recently, abundant axial tubule (AT) membrane structures were identified deep inside atrial myocytes (AMs). Upon excitation, ATs rapidly activate intracellular Ca2+ release and sarcomeric contraction through extensive AT junctions, a cell-specific atrial mechanism. While AT junctions with the sarcoplasmic reticulum contain unusually large clusters of ryanodine receptor 2 (RyR2) Ca2+ release channels in mouse AMs, it remains unclear if similar protein networks and membrane structures exist across species, particularly those relevant for atrial disease modeling. Objective: To examine and quantitatively analyze the architecture of AT membrane structures and associated Ca2+ signaling proteins across species from mouse to human. Methods and Results: We developed superresolution microscopy (nanoscopy) strategies for intact live AMs based on a new custom-made photostable cholesterol dye and immunofluorescence imaging of membraneous structures and membrane proteins in fixed tissue sections from human, porcine, and rodent atria. Consistently, in mouse, rat, and rabbit AMs, intact cell-wide tubule networks continuous with the surface membrane were observed, mainly composed of ATs. Moreover, co-immunofluorescence nanoscopy showed L-type Ca2+ channel clusters adjacent to extensive junctional RyR2 clusters at ATs. However, only junctional RyR2 clusters were highly phosphorylated and may thus prime Ca2+ release at ATs, locally for rapid signal amplification. While the density of the integrated L-type Ca2+ current was similar in human and mouse AMs, the intracellular Ca2+ transient showed quantitative differences. Importantly, local intracellular Ca2+ release from AT junctions occurred through instantaneous action potential propagation via transverse tubules (TTs) from the surface membrane. Hence, sparse TTs were sufficient as electrical conduits for rapid activation of Ca2+ release through ATs. Nanoscopy of atrial tissue sections confirmed abundant ATs as the major network component of AMs, particularly in human atrial tissue sections. Conclusion: AT junctions represent a conserved, cell-specific membrane structure for rapid excitation-contraction coupling throughout a representative spectrum of species including human. Since ATs provide the major excitable membrane network component in AMs, a new model of atrial \"super-hub\" Ca2+ signaling may apply across biomedically relevant species, opening avenues for future investigations about atrial disease mechanisms and therapeutic targeting."],["dc.identifier.doi","10.3389/fphys.2018.01227"],["dc.identifier.pmid","30349482"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15400"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/107860"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/217"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A05: Molekulares Imaging von kardialen Calcium-Freisetzungsdomänen"],["dc.relation","SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion"],["dc.relation","SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse"],["dc.relation","SFB 1002 | A13: Bedeutung einer gestörten zytosolischen Calciumpufferung bei der atrialen Arrhythmogenese bei Patienten mit Herzinsuffizienz (HF)"],["dc.relation.eissn","1664-042X"],["dc.relation.workinggroup","RG Brandenburg"],["dc.relation.workinggroup","RG Lehnart (Cellular Biophysics and Translational Cardiology Section)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Axial Tubule Junctions Activate Atrial Ca2+ Release across Species"],["dc.type","research_data"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1882"],["dc.bibliographiccitation.issue","7, Part B"],["dc.bibliographiccitation.lastpage","1893"],["dc.bibliographiccitation.volume","1863"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Arakel, Eric C."],["dc.contributor.author","Schwappach, Blanche"],["dc.contributor.author","Lehnart, Stephan E."],["dc.date.accessioned","2017-09-07T11:44:49Z"],["dc.date.available","2017-09-07T11:44:49Z"],["dc.date.issued","2016"],["dc.description.abstract","Atrial cardiomyocytes are essential for fluid homeostasis, ventricular filling, and survival, yet their cell biology and physiology are incompletely understood. It has become clear that the cell fate of atrial cardiomyocytes depends significantly on transcription programs that might control thousands of differentially expressed genes. Atrial muscle membranes propagate action potentials and activate myofilament force generation, producing overall faster contractions than ventricular muscles. While atria-specific excitation and contractility depend critically on intracellular Ca2+ signalling, voltage-dependent L-type Ca2+ channels and ryanodine receptor Ca2+ release channels are each expressed at high levels similar to ventricles. However, intracellular Ca2+ transients in atrial cardiomyocytes are markedly heterogeneous and fundamentally different from ventricular cardiomyocytes. In addition, differential atria-specific K+ channel expression and trafficking confer unique electrophysiological and metabolic properties. Because diseased atria have the propensity to perpetuate fast arrhythmias, we discuss our understanding about the cell-specific mechanisms that lead to metabolic and/or mitochondrial dysfunction in atrial fibrillation. Interestingly, recent work identified potential atria-specific mechanisms that lead to early contractile dysfunction and metabolic remodelling, suggesting highly interdependent metabolic, electrical, and contractile pathomechanisms. Hence, the objective of this review is to provide an integrated model of atrial cardiomyocytes, from tissue-specific cell properties, intracellular metabolism, and excitation-contraction (EC) coupling to early pathological changes, in particular metabolic dysfunction and tissue remodelling due to atrial fibrillation and aging. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. (c) 2015 Published by Elsevier B.V."],["dc.identifier.doi","10.1016/j.bbamcr.2015.11.025"],["dc.identifier.gro","3141657"],["dc.identifier.isi","000378360400022"],["dc.identifier.pmid","26620800"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/6120"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/108"],["dc.language.iso","en"],["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","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A07: Rolle der TRC40-Maschinerie im Proteostase-Netzwerk von Kardiomyozyten"],["dc.relation","SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion"],["dc.relation.conference","8th Ascona International Workshop on Cardiomyocyte Biology - Integration of Developmental and Environmental Cues"],["dc.relation.eissn","0006-3002"],["dc.relation.eventend","2015-05-03"],["dc.relation.eventlocation","Ascona, SWITZERLAND"],["dc.relation.eventstart","2015-05-03"],["dc.relation.ispartof","Biochimica et Biophysica Acta (BBA) - Molecular Cell Research"],["dc.relation.issn","0167-4889"],["dc.relation.workinggroup","RG Brandenburg"],["dc.relation.workinggroup","RG Lehnart (Cellular Biophysics and Translational Cardiology Section)"],["dc.relation.workinggroup","RG Schwappach (Membrane Protein Biogenesis)"],["dc.title","The molecular and functional identities of atrial cardiomyocytes in health and disease"],["dc.type","conference_paper"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3999"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Journal of Clinical Investigation"],["dc.bibliographiccitation.lastpage","4015"],["dc.bibliographiccitation.volume","126"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Kohl, Tobias"],["dc.contributor.author","Williams, George S. B."],["dc.contributor.author","Gusev, Konstantin"],["dc.contributor.author","Wagner, Eva"],["dc.contributor.author","Rog-Zielinska, Eva A."],["dc.contributor.author","Hebisch, Elke"],["dc.contributor.author","Dura, Miroslav"],["dc.contributor.author","Didié, Michael"],["dc.contributor.author","Gotthardt, Michael"],["dc.contributor.author","Nikolaev, Viacheslav O."],["dc.contributor.author","Kohl, Peter"],["dc.contributor.author","Ward, Christopher W."],["dc.contributor.author","Lederer, W. Jonathan"],["dc.contributor.author","Lehnart, Stephan E."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.date.accessioned","2020-12-10T18:38:18Z"],["dc.date.available","2020-12-10T18:38:18Z"],["dc.date.issued","2016"],["dc.description.abstract","The canonical atrial myocyte (AM) is characterized by sparse transverse tubule (TT) invaginations and slow intracellular Ca2+ propagation but exhibits rapid contractile activation that is susceptible to loss of function during hypertrophic remodeling. Here, we have identified a membrane structure and Ca2+-signaling complex that may enhance the speed of atrial contraction independently of phospholamban regulation. This axial couplon was observed in human and mouse atria and is composed of voluminous axial tubules (ATs) with extensive junctions to the sarcoplasmic reticulum (SR) that include ryanodine receptor 2 (RyR2) clusters. In mouse AM, AT structures triggered Ca2+ release from the SR approximately 2 times faster at the AM center than at the surface. Rapid Ca2+ release correlated with colocalization of highly phosphorylated RyR2 clusters at AT-SR junctions and earlier, more rapid shortening of central sarcomeres. In contrast, mice expressing phosphorylation-incompetent RyR2 displayed depressed AM sarcomere shortening and reduced in vivo atrial contractile function. Moreover, left atrial hypertrophy led to AT proliferation, with a marked increase in the highly phosphorylated RyR2-pS2808 cluster fraction, thereby maintaining cytosolic Ca2+ signaling despite decreases in RyR2 cluster density and RyR2 protein expression. AT couplon \"super-hubs\" thus underlie faster excitation-contraction coupling in health as well as hypertrophic compensatory adaptation and represent a structural and metabolic mechanism that may contribute to contractile dysfunction and arrhythmias."],["dc.identifier.doi","10.1172/JCI88241"],["dc.identifier.gro","3141610"],["dc.identifier.isi","000384703300035"],["dc.identifier.pmid","27643434"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77268"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/151"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A01: cAMP- und cGMP- Mikrodomänen bei Herzhypertrophie und Insuffizienz"],["dc.relation","SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion"],["dc.relation","SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle"],["dc.relation","SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse"],["dc.relation","SFB 1002 | Z: Zentrale Organisation und Verwaltung"],["dc.relation.eissn","1558-8238"],["dc.relation.issn","0021-9738"],["dc.relation.workinggroup","RG Brandenburg"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Lehnart (Cellular Biophysics and Translational Cardiology Section)"],["dc.relation.workinggroup","RG Nikolaev (Cardiovascular Research Center)"],["dc.title","Axial tubule junctions control rapid calcium signaling in atria"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","141"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","157"],["dc.bibliographiccitation.volume","165"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Pawlowitz, Jan"],["dc.contributor.author","Steckmeister, Vanessa"],["dc.contributor.author","Subramanian, Hariharan"],["dc.contributor.author","Uhlenkamp, Dennis"],["dc.contributor.author","Scardigli, Marina"],["dc.contributor.author","Mushtaq, Mufassra"],["dc.contributor.author","Amlaz, Saskia I."],["dc.contributor.author","Kohl, Tobias"],["dc.contributor.author","Wegener, Jörg W."],["dc.contributor.author","Lehnart, Stephan E."],["dc.date.accessioned","2022-02-01T10:32:12Z"],["dc.date.available","2022-02-01T10:32:12Z"],["dc.date.issued","2022"],["dc.description.abstract","Axial tubule junctions with the sarcoplasmic reticulum control the rapid intracellular Ca2+-induced Ca2+ release that initiates atrial contraction. In atrial myocytes we previously identified a constitutively increased ryanodine receptor (RyR2) phosphorylation at junctional Ca2+ release sites, whereas non-junctional RyR2 clusters were phosphorylated acutely following β-adrenergic stimulation. Here, we hypothesized that the baseline synthesis of 3′,5′-cyclic adenosine monophosphate (cAMP) is constitutively augmented in the axial tubule junctional compartments of atrial myocytes. Confocal immunofluorescence imaging of atrial myocytes revealed that junctin, binding to RyR2 in the sarcoplasmic reticulum, was densely clustered at axial tubule junctions. Interestingly, a new transgenic junctin-targeted FRET cAMP biosensor was exclusively co-clustered in the junctional compartment, and hence allowed to monitor cAMP selectively in the vicinity of junctional RyR2 channels. To dissect local cAMP levels at axial tubule junctions versus subsurface Ca2+ release sites, we developed a confocal FRET imaging technique for living atrial myocytes. A constitutively high adenylyl cyclase activity sustained increased local cAMP levels at axial tubule junctions, whereas β-adrenergic stimulation overcame this cAMP compartmentation resulting in additional phosphorylation of non-junctional RyR2 clusters. Adenylyl cyclase inhibition, however, abolished the junctional RyR2 phosphorylation and decreased L-type Ca2+ channel currents, while FRET imaging showed a rapid cAMP decrease. In conclusion, FRET biosensor imaging identified compartmentalized, constitutively augmented cAMP levels in junctional dyads, driving both the locally increased phosphorylation of RyR2 clusters and larger L-type Ca2+ current density in atrial myocytes. This cell-specific cAMP nanodomain is maintained by a constitutively increased adenylyl cyclase activity, contributing to the rapid junctional Ca2+-induced Ca2+ release, whereas β-adrenergic stimulation overcomes the junctional cAMP compartmentation through cell-wide activation of non-junctional RyR2 clusters."],["dc.identifier.doi","10.1016/j.yjmcc.2022.01.003"],["dc.identifier.pii","S0022282822000062"],["dc.identifier.pmid","35033544"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/99034"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/391"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/414"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/168"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-517"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","SFB 1190 | P03: Erhaltung und funktionelle Kopplung von ER-Kontakten mit der Plasmamembran"],["dc.relation.issn","0022-2828"],["dc.relation.workinggroup","RG Hasenfuß"],["dc.relation.workinggroup","RG Lehnart"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.relation.workinggroup","RG Brandenburg"],["dc.relation.workinggroup","RG Nikolaev (Cardiovascular Research Center)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","A junctional cAMP compartment regulates rapid Ca2+ signaling in atrial myocytes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]