Brandenburg, Sören

[["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.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","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"]]

[["dc.bibliographiccitation.firstpage","2106"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Journal of Cell Science"],["dc.bibliographiccitation.lastpage","2119"],["dc.bibliographiccitation.volume","127"],["dc.contributor.author","Arakel, Eric C."],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Uchida, Keita"],["dc.contributor.author","Zhang, Haixia"],["dc.contributor.author","Lin, Yu-Wen"],["dc.contributor.author","Kohl, Tobias"],["dc.contributor.author","Schrul, Bianca"],["dc.contributor.author","Sulkin, Matthew S."],["dc.contributor.author","Efimov, Igor R."],["dc.contributor.author","Nichols, Colin G."],["dc.contributor.author","Lehnart, Stephan E."],["dc.contributor.author","Schwappach, Blanche"],["dc.date.accessioned","2017-09-07T11:46:16Z"],["dc.date.available","2017-09-07T11:46:16Z"],["dc.date.issued","2014"],["dc.description.abstract","The copy number of membrane proteins at the cell surface is tightly regulated. Many ion channels and receptors present retrieval motifs to COPI vesicle coats and are retained in the early secretory pathway. In some cases, the interaction with COPI is prevented by binding to 14-3- 3 proteins. However, the functional significance of this antagonism between COPI and 14-3-3 in terminally differentiated cells is unknown. Here, we show that ATP-sensitive K+ (K-ATP) channels, which are composed of Kir6.2 and SUR1 subunits, are stalled in the Golgi complex of ventricular, but not atrial, cardiomyocytes. Upon sustained beta-adrenergic stimulation, which leads to activation of protein kinase A (PKA), SUR1-containing channels reach the plasma membrane of ventricular cells. We show that PKA-dependent phosphorylation of the C-terminus of Kir6.2 decreases binding to COPI and, thereby, silences the arginine-based retrieval signal. Thus, activation of the sympathetic nervous system releases this population of KATP channels from storage in the Golgi and, hence, might facilitate the adaptive response to metabolic challenges."],["dc.identifier.doi","10.1242/jcs.141440"],["dc.identifier.gro","3142132"],["dc.identifier.isi","000335814800021"],["dc.identifier.pmid","24569881"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10660"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/4900"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/3"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A05: Molekulares Imaging von kardialen Calcium-Freisetzungsdomänen"],["dc.relation","SFB 1002 | A07:Rolle der TRC40-Maschinerie im Proteostase-Netzwerk von Kardiomyozyten"],["dc.relation.eissn","1477-9137"],["dc.relation.issn","0021-9533"],["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.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","Tuning the electrical properties of the heart by differential trafficking of K-ATP ion channel complexes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]