@article{PoppSchmittBoehrerLangeretal.2021, author = {Popp, Sandy and Schmitt-B{\"o}hrer, Angelika and Langer, Simon and Hofmann, Ulrich and Hommers, Leif and Schuh, Kai and Frantz, Stefan and Lesch, Klaus-Peter and Frey, Anna}, title = {5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction}, series = {Journal of Clinical Medicine}, volume = {10}, journal = {Journal of Clinical Medicine}, number = {14}, issn = {2077-0383}, doi = {10.3390/jcm10143104}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242739}, year = {2021}, abstract = {Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally na{\"i}ve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (-/-) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT-/- mice with infarct sizes >30\% experienced 100\% mortality, while 50\% of 5-HTT+/- and 37\% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30\%) 5-HTT-/- mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT-/- mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.}, language = {en} } @article{FreyPoppPostetal.2014, author = {Frey, Anna and Popp, Sandy and Post, Antonia and Langer, Simon and Lehmann, Marc and Hofmann, Ulrich and Siren, Anna-Leena and Hommers, Leif and Schmitt, Angelika and Strekalova, Tatyana and Ertl, Georg and Lesch, Klaus-Peter and Frantz, Stefan}, title = {Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain}, series = {Frontiers in Behavioral Neuroscience}, volume = {8}, journal = {Frontiers in Behavioral Neuroscience}, issn = {1662-5153}, doi = {10.3389/fnbeh.2014.00376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118234}, pages = {376}, year = {2014}, abstract = {Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression.}, language = {en} } @article{WieseDennstaedtHollmannetal.2021, author = {Wiese, Teresa and Dennst{\"a}dt, Fabio and Hollmann, Claudia and Stonawski, Saskia and Wurst, Catherina and Fink, Julian and Gorte, Erika and Mandasari, Putri and Domschke, Katharina and Hommers, Leif and Vanhove, Bernard and Schumacher, Fabian and Kleuser, Burkard and Seibel, J{\"u}rgen and Rohr, Jan and Buttmann, Mathias and Menke, Andreas and Schneider-Schaulies, J{\"u}rgen and Beyersdorf, Niklas}, title = {Inhibition of acid sphingomyelinase increases regulatory T cells in humans}, series = {Brain Communications}, volume = {3}, journal = {Brain Communications}, number = {2}, doi = {10.1093/braincomms/fcab020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259868}, year = {2021}, abstract = {Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro.}, language = {en} } @phdthesis{Hommers2008, author = {Hommers, Leif}, title = {Modulation der Einw{\"a}rtsgleichrichrichtung von GIRK-Kan{\"a}len durch G-Protein Untereinheiten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-40388}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {G-Protein-gekoppelte einw{\"a}rtsgleichrichtende Kalium-Kan{\"a}le sind durch zwei Eigenschaften gekennzeichnet: (I) Die Leitf{\"a}higkeit f{\"u}r K+-Ionen ist positiv des Kalium-Gleichgewichtspotentials reduziert und (II) die Kanal-Aktivit{\"a}t wird durch Bindung von G betagamma-Dimere heterotrimerer Gi/o-Proteine reguliert. In der Literatur wurde die Aktivierung von GIRK-Kan{\"a}len als eine Zunahme ihrer Offenwahrscheinlichkeit unabh{\"a}ngig vom Membranpotential beschrieben. Die vorliegenden Untersuchungen zeigten, dass es bei starker Aktivierung des GIRK-Kanals durch G betagamma-Dimere auch zu einer Abschw{\"a}chung der Einw{\"a}rtsgleichrichtung kommt. Im heterologen Expressionssystem konnte bei Rezeptor-Stimulation mit Agonist die Einw{\"a}rtsgleichrichtung von GIRK-Kan{\"a}len abh{\"a}ngig von der St{\"a}rke der Koexpression von G betagamma-Dimeren geschw{\"a}cht werden. Dieser Effekt entstand nicht durch eine Ver{\"a}nderung der Affinit{\"a}t, mit der Polyamine und Mg2+-Ionen den GIRK-Kanal membranpotentialabh{\"a}ngig blockieren. Die Kinetik, mit der Polyamine den GIRK-Kanal blockieren, war nicht ver{\"a}ndert; eine Erh{\"o}hung der intrazellul{\"a}ren Mg2+-Konzentration um den Faktor 20 konnte eine Abschw{\"a}chung der Einw{\"a}rtsgleichrichtung nicht mindern. Es wurde vermutet, dass eine {\"A}nderung der Konformation von Strukturen nahe des Selektivit{\"a}tsfilters die Abschw{\"a}chung der Einw{\"a}rtsgleichrichtung verursacht. Gest{\"u}tzt wurde diese Vermutung zum einen dadurch, dass Ba2+- und Cs+-Ionen, die von extrazellul{\"a}rer Seite her den Kanal an Strukturen nahe des Selektivit{\"a}tsfilters blockieren k{\"o}nnen, unter schwach einw{\"a}rtsgleichrichtenden Bedingungen eine geringere Bindungsaffinit{\"a}t hatten und zum anderen dadurch, dass das relative Ausmaß des GIRK-Kanal-Blocks durch Cs+-Ionen mit der St{\"a}rke der Einw{\"a}rtsgleichrichtung korrelierte.}, subject = {GIRK}, language = {de} } @article{KlenkHommersLohse2022, author = {Klenk, Christoph and Hommers, Leif and Lohse, Martin J.}, title = {Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone 1 receptor}, series = {Frontiers in Endocrinology}, volume = {13}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2022.839351}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262055}, year = {2022}, abstract = {Parathyroid hormone 1 receptor (PTH1R) is a member of the class B family of G protein-coupled receptors, which are characterized by a large extracellular domain required for ligand binding. We have previously shown that the extracellular domain of PTH1R is subject to metalloproteinase cleavage in vivo that is regulated by ligand-induced receptor trafficking and leads to impaired stability of PTH1R. In this work, we localize the cleavage site in the first loop of the extracellular domain using amino-terminal protein sequencing of purified receptor and by mutagenesis studies. We further show, that a receptor mutant not susceptible to proteolytic cleavage exhibits reduced signaling to G\(_s\) and increased activation of G\(_q\) compared to wild-type PTH1R. These findings indicate that the extracellular domain modulates PTH1R signaling specificity, and that its cleavage affects receptor signaling.}, language = {en} } @phdthesis{Hommers2011, author = {Hommers, Leif}, title = {{\"U}ber die Interaktion aktivierter G-Proteine mit G-Protein gekoppelten Rezeptoren}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-56576}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Aktivierte G-Protein gekoppelte Rezeptoren aktivieren heterotrimere GProteine, in dem sie den Austausch von GDP zu GTP am G-Protein katalysieren. Theoretische Untersuchungen mittels eines vereinfachten kinetischen Modells des Gi/o-Protein Zyklus legen nahe, dass nicht nur GDP-,sondern auch GTP-gebundene Gi/o-Proteine mit aktivierten α2A-adrenergen Rezeptoren (α2A-AR) interagieren k{\"o}nnen. Demgem{\"a}ß sollten aktivierte Gi/o-Proteine mit aktivierten α2A-AR vermehrt interagieren, wenn mehr α2A-AR aktiviert werden als f{\"u}r eine maximale G-Protein Aktivierung n{\"o}tig sind. Dies sollte zu einer paradoxen Deaktivierung von Gi/o-Proteinen und deren Effektorproteinen, z.B. dem G-Protein gekoppelten, einw{\"a}rtsgleichrichtenden Kaliumkanal (GIRK-Kanal) f{\"u}hren. Mittels FRET l{\"a}sst sich in lebenden und in permeabilisierten Zellen unter Kontrolle der intrazellul{\"a}ren Nukleotide die Aktivierung von α2A-AR, die Interaktion von Gi/o-Proteinen mit α2A-AR und die Aktivierung von Gi/o-Proteinen bestimmen. Die Arbeit zeigt auf mehreren Ebenen, dass Go-Proteine mit aktivierten α2A-AR interagieren und im nukleotidfreiem Zustand sequestriert werden k{\"o}nnen: (I) Go-Proteine,irreversibel durch GTPγS aktiviert werden abh{\"a}ngig von der Rezeptor Aktivierung in Abwesenheit von Nukleotiden deaktiviert, (II) Go-Proteine interagieren in Gegenwart niedriger Nukleotidkonzentrationen in wesentlich gr{\"o}ßer Fraktion mit aktivierten α2A-AR als in Gegenwart hoher Nukleotidkonzentrationen, (III) Go Proteine k{\"o}nnen in Gegenwart niedriger GTP und GTPγS-Konzentrationen bei Aktivierung des α2A-AR inaktiviert werden. Die Arbeit zeigt exemplarisch an der Signalkaskade des α2A-AR und Go, dass der G-Protein Zyklus in lebenden Zellen reversibel ist, woraus eine Deaktivierung aktivierter G-Proteine und aktivierter G-Protein Effektoren resultieren kann. Dies erkl{\"a}rt paradoxe Befunde zur Deaktivierung von GIRK-Kan{\"a}len in Myozyten durch A1-Rezeptoren.}, subject = {G-Protein gekoppelte Rezeptoren}, language = {de} }