Biology subjects

Sauer, J.

Publications and source records attributed to Sauer, J..

5 recordsLinked to original sources

bioRxiv2025

Crosstalk of noradrenergic Ca2+ and cAMP signaling in astrocytes of the murine olfactory bulb

Cyclic adenosine monophosphate (cAMP) and Ca2+ are ubiquitous second messengers that regulate gene expression, metabolism, and synaptic plasticity. Here, we identified a complex interplay between Ca2+ and cAMP signaling pathways in mouse olfactory bulb astrocytes. Norepinephrine (NE) elevated both Ca2+ and cAMP levels via 1 and 2 adrenergic receptors, whereas {beta} receptors triggered only cAMP responses. The 1 receptor agonist phenylephrine increased cAMP, but this effect was suppressed when Ca2+ elevations were blocked by Ca2+ depletion and removal of external Ca2+. We found that 1A and 1D receptors are key targets for phenylephrine, acting through Ca2+/calmodulin-dependent adenylyl cyclases AC1 and AC3 downstream of 1 receptor activation. Moreover, 2 receptor stimulation raised Ca2+ levels, thereby stimulating cAMP production, yet also reduced forskolin-induced cAMP elevations, indicating that 2 receptors can both inhibit adenylyl cyclase via Gi and stimulate AC1/AC3 via Ca2+ signaling. Together, these findings reveal intricate crosstalk between noradrenergic Ca2+ and cAMP signaling in olfactory bulb astrocytes mediated by all three adrenergic receptor subtypes.

neuroscience↗

bioRxiv2025

The sodium/glucose cotransporter 2 inhibitor empagliflozin is a pharmacological chaperone of cardiac Nav1.5 channels

Diminished peak sodium current (INa) is a causative factor for slowed ventricular conduction and cardiac arrhythmias in patients with Duchenne muscular dystrophy (DMD), a devastating muscle disease triggered by dystrophin deficiency. Recently, we showed that chronic administration of the sodium/glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) restores diminished peak INa in ventricular cardiomyocytes from the dystrophin-deficient mdx mouse model of DMD. Here, we aimed to elucidate the underlying mechanism. Whole cell patch clamp studies revealed that 24 h incubation of dystrophic (mdx) ventricular cardiomyocytes with EMPA significantly increases peak INa in a concentration-dependent manner (EC50=94 nM). The enhancing effect on peak INa also occurred in dystrophic cardiac Purkinje fibers, Nav1.5-expressing tsA201 cells, as well as in dystrophic (DMDmdx) rat cardiomyocytes, and was also exerted by two other SGLT2 inhibitors. Immunofluorescence studies suggested that chronic EMPA treatment increases Nav1.5 plasma membrane expression. Peak INa enhancement by EMPA depended on functional anterograde trafficking of Nav1.5. The local anesthetic mexiletine, a well-known pharmacological chaperone of Nav1.5, enhanced peak INa in a similar manner as EMPA. Further, mutation of human Nav1.5 at a site important for local anesthetic binding (Y1767A) completely abolished the ability of both EMPA and mexiletine to enhance peak INa. Finally, the importance of Y1767 for drug-induced modulation of peak INa was confirmed by molecular docking simulations. Our findings suggest that EMPA acts as a pharmacological chaperone of Nav1.5 channels. Its chronic administration may reduce arrhythmia vulnerability in patients with DMD and other arrhythmogenic pathologies associated with diminished peak INa.

pharmacology and toxicology↗

bioRxiv2024

Staphylococcus aureus lipid factors modulate melanoma clustering and invasion in zebrafish

The microbiome can influence cancer development and progression. However, less is known about the role of the skin microbiota in melanoma. Here, we take advantage of a zebrafish melanoma model to probe the effects of Staphylococcus aureus on melanoma invasion. We find that S. aureus produces factors that enhance melanoma invasion and dissemination in zebrafish larvae. We used a published in vitro 3D cluster formation assay which correlates increased clustering with tumor invasion. S. aureus supernatant increased clustering of melanoma cells which was abrogated by use of a Rho-Kinase inhibitor, implicating a role for Rho-GTPases. The melanoma clustering response was specific to S. aureus and not other staphylococcal species, including S. epidermidis. Our findings suggest that S. aureus may promote melanoma clustering and invasion via lipids generated by the lipase SAL2 (gehB). Taken together, these findings suggest that specific bacterial products mediate melanoma invasive migration in zebrafish. Summary statementS. aureus supernatant increases melanoma invasion in zebrafish and is likely mediated by production of bacterial lipids.

cancer biology↗

bioRxiv2022

Triple COVID-19 vaccination induces humoral and cellular immunity to SARS-CoV-2 with cross-recognition of the Omicron variant and IgA secretion

COVID-19 vaccination is the leading strategy to prevent severe courses after SARS-CoV-2 infection. In our study, we analyzed humoral and cellular immune responses in detail to three consecutive homologous or heterologous COVID-19 vaccinations. All individuals (n=20) responded to vaccination with increasing S1- /RBD-/S2-specific IgG levels, whereas specific plasma IgA displayed individual variability. The third dose increased antibody inhibitory capacity (AIC) against immune-escape variants Beta and Omicron independently from age. The mRNA-primed vaccination induced IgG and IgA immunity more efficiently, whereas vector-primed individuals displayed higher levels of memory T and B cells. Vaccinees showed a SARS-CoV-2-specific T cell responses, which were further improved and specified after Omicron breakthrough infections in parallel to appearance of new variant-specific antibodies. In conclusion, the third vaccination was essential to increase IgG levels, mandatory to boost AIC against immune-escape variants and induced SARS-CoV-2-specific T cells. Breakthrough infection with Omicron generates additional spike specificities covering all known variants.

immunology↗

bioRxiv2019

Multiparametric phenotyping of compound effects on patient derived organoids

Patient derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases from primary patient samples. Organoids can be used as models for drug discovery and are being explored to guide clinical decision making. Patient derived organoids can have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we used high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with more than 500 small molecules. Integration of data using a joint multi-omics modelling framework identified organoid size and cystic vs. solid organoid architecture as axes of morphological variation across organoids. Mechanistically, we found that organoid size was linked to IGF1 receptor signaling, while a cystic organoid architecture was associated with an LGR5+ stemness program. Treatment-induced organoid morphology reflected organoid viability, drug mechanism of action, and was biologically interpretable using joint modelling. Inhibition of MEK led to cystic reorganization of organoids and increased expression of LGR5, while inhibition of mTOR induced IGF1 receptor signaling. In conclusion, we identified shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. Image-based profiling of patient derived organoids coupled with multi-omics integration facilitates drug discovery by linking drug responses with underlying biological mechanisms.

genomics↗