Recent advances in our understanding of the structure and function of more unusual cation channels.

As their name implies, cation channels allow the regulated flow of cations such as sodium, potassium, calcium, and magnesium across cellular and intracellular membranes. Cation channels have long been known for their fundamental roles in controlling membrane potential and excitability in neurons and muscle. In this review, we provide an update on the recent advances in our understanding of the structure-function relationship and the physiological and pathophysiological role of cation channels. The most exciting developments in the last two years, in our opinion, have been the insights that cryoelectron microscopy has provided into the inner life and the gating of not only voltage-gated channels but also mechanosensitive and calcium- or sodium-activated channels. The mechanosensitive Piezo channels especially have delighted the field not only with a fascinating new type of structure but with important roles in blood pressure regulation and lung function

Gesund Aufwachsen - Sichtweisen und Bedürfnisse von Eltern 2- bis 6-jähriger Kinder in Charlottenburg-Nord

Als universitäre Fachrichtung wurde Public Health in Deutschland Ende der neunziger Jahre federführend durch die Deutsche Gesellschaft für Public Health e. V. etabliert und ist damit gegenwärtig noch immer eine vergleichsweise „junge“ akademische Qualifikation im dreistufigen Studiensystem aus Bachelor, Master und Promotion. Auf der Grundlage einer Berufsausbildung in den ausgewählten Gesundheitsfachberufen Altenpflege, Diätassistenz, Ergotherapie, Gesundheits- und (Kinder)Krankenpflege, Entbindungspflege, Logopädie, Rettungsdienst, Orthoptik und Physiotherapie (Charité-Universitätsmedizin Berlin (CUB) 2018) zielt der im Jahr 2011 an der Charité – Universitätsmedizin Berlin erstmals angebotene Bachelorstudiengang Gesundheitswissenschaften auf den Erwerb breit angelegter fachwissenschaftlicher und methodischer Kompetenzen zur Übernahme von qualifizierten Fachfunktionen in unterschiedlichen gesundheitswissenschaftlichen Handlungsfeldern. Der Studienabschluss bahnt Wege in verschiedene gesundheitswissenschaftliche Tätigkeitsbereiche auf mittlerer Handlungs-, Entscheidungs- und Verantwortungsebene (CUB 2017). Zu den zukünftigen Aufgaben der Absolvent*innen zählen beispielsweise die multidisziplinäre Planung, Entwicklung und Umsetzung von gesundheitsrelevanten populationsbezogenen Initiativen und Programmen in der Gesundheitsverwaltung, in Versicherungen, Behörden und Gesundheitseinrichtungen, der gesundheitsbezogenen Öffentlichkeits- und außerschulischen Bildungsarbeit, der Gesundheitsförderung und Krankheitsprävention oder auch die Mitwirkung an Aktivitäten der angewandten Gesundheitsforschung. Vor dem Hintergrund der Erschließung neuer Berufsfelder und der stetigen Entwicklung neuer Aufgabenbereiche für Bachelorabsolventinnen und -absolventen der Gesundheitswissenschaften spielt das Modul B18 „Spezielle Themen der Gesundheitswissenschaften“ eine bedeutende Rolle. Ziel dieses Moduls ist die projektförmige und praxisnahe Bearbeitung wechselnder gesundheitswissenschaftlicher Frage- und Problemstellungen. Besonderes Augenmerk wird auf die Heranziehung multidisziplinärer Sichtweisen bei der Problembearbeitung gelegt, wobei die unterschiedlichen beruflichen Erfahrungen der Studierenden und die im Studium erworbenen Kompetenzen einen wichtigen Beitrag für konstruktive Diskussionen innerhalb der Seminare leisten. Die Studierenden haben die Wahl zwischen wechselnden Themen der Gesundheitswissenschaften. Im Wintersemester 2018/19 wurden Seminare zu den Themenschwerpunkten ..

The Trials and Tribulations of Structure Assisted Design of KCa Channel Activators.

Calcium-activated K+ channels constitute attractive targets for the treatment of neurological and cardiovascular diseases. To explain why certain 2-aminobenzothiazole/oxazole-type KCa activators (SKAs) are KCa3.1 selective we previously generated homology models of the C-terminal calmodulin-binding domain (CaM-BD) of KCa3.1 and KCa2.3 in complex with CaM using Rosetta modeling software. We here attempted to employ this atomistic level understanding of KCa activator binding to switch selectivity around and design KCa2.2 selective activators as potential anticonvulsants. In this structure-based drug design approach we used RosettaLigand docking and carefully compared the binding poses of various SKA compounds in the KCa2.2 and KCa3.1 CaM-BD/CaM interface pocket. Based on differences between residues in the KCa2.2 and KCa.3.1 models we virtually designed 168 new SKA compounds. The compounds that were predicted to be both potent and KCa2.2 selective were synthesized, and their activity and selectivity tested by manual or automated electrophysiology. However, we failed to identify any KCa2.2 selective compounds. Based on the full-length KCa3.1 structure it was recently demonstrated that the C-terminal crystal dimer was an artefact and suggested that the "real" binding pocket for the KCa activators is located at the S4-S5 linker. We here confirmed this structural hypothesis through mutagenesis and now offer a new, corrected binding site model for the SKA-type KCa channel activators. SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine) is binding in the interface between the CaM N-lobe and the S4-S5 linker where it makes van der Waals contacts with S181 and L185 in the S45A helix of KCa3.1

Alpha1 -adrenergic stimulation selectively enhances endothelium-mediated vasodilation in rat cremaster arteries.

We have systematically investigated how vascular smooth muscle α1 -adrenoceptor activation impacts endothelium-mediated vasodilation in isolated, myogenically active, rat cremaster muscle 1A arteries. Cannulated cremaster arteries were pressurized intraluminally to 70 mmHg to induce myogenic tone, and exposed to vasoactive agents via bath superfusion at 34°C. Smooth muscle membrane potential was measured via sharp microelectrode recordings in pressurized, myogenic arteries. The α1 -adrenergic agonist phenylephrine (25-100 nmol/L) produced further constriction of myogenic arteries, but did not alter the vasorelaxant responses to acetylcholine (0.3 μmol/L), SKA-31 (an activator of endothelial Ca2+ -dependent K+ channels) (3 μmol/L) or sodium nitroprusside (10 μmol/L). Exposure to 0.25-1 μmol/L phenylephrine or 1 μmol/L norepinephrine generated more robust constrictions, and also enhanced the vasodilations evoked by acetylcholine and SKA-31, but not by sodium nitroprusside. In contrast, the thromboxane receptor agonist U46619 (250 nmol/L) dampened responses to all three vasodilators. Phenylephrine exposure depolarized myogenic arteries, and mimicking this effect with 4-aminopyridine (1 mmol/L) was sufficient to augment the SKA-31-evoked vasodilation. Inhibition of L-type Ca2+ channels by 1 μmol/L nifedipine decreased myogenic tone, phenylephrine-induced constriction and prevented α1 -adrenergic enhancement of endothelium-evoked vasodilation; these latter deficits were overcome by exposure to 3 and 10 μmol/L phenylephrine. Mechanistically, augmentation of ACh-evoked dilation by phenylephrine was dampened by eNOS inhibition and abolished by blockade of endothelial KCa channels. Collectively, these data suggest that increasing α1 -adrenoceptor activation beyond a threshold level augments endothelium-evoked vasodilation, likely by triggering transcellular signaling between smooth muscle and the endothelium. Physiologically, this negative feedback process may serve as a "brake" to limit the extent of vasoconstriction in the skeletal microcirculation evoked by the elevated sympathetic tone

Microglial KCa3.1 Channels as a Potential Therapeutic Target for Alzheimer's Disease

There exists an urgent need for new target discovery to treat Alzheimer's disease (AD); however, recent clinical trials based on anti-Aβ and anti-inflammatory strategies have yielded disappointing results. To expedite new drug discovery, we propose reposition targets which have been previously pursued by both industry and academia for indications other than AD. One such target is the calcium-activated potassium channel KCa3.1 (KCNN4), which in the brain is primarily expressed in microglia and is significantly upregulated when microglia are activated. We here review the existing evidence supporting that KCa3.1 inhibition could block microglial neurotoxicity without affecting their neuroprotective phagocytosis activity and without being broadly immunosuppressive. The anti-inflammatory and neuroprotective effects of KCa3.1 blockade would be suitable for treating AD as well as cerebrovascular and traumatic brain injuries, two well-known risk factors contributing to the dementia in AD patients presenting with mixed pathologies. Importantly, the pharmacokinetics and pharmacodynamics of several KCa3.1 blockers are well known, and a KCa3.1 blocker has been proven safe in clinical trials. It is therefore promising to reposition old or new KCa3.1 blockers for AD preclinical and clinical trials