K channel targeting impairs DNA repair and invasiveness of patient-derived glioblastoma stem cells in culture and orthotopic mouse xenografts which only in part is predictable by K expression levels.

Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion.

Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine-Independent and Chronic Itch.

Various disorders are accompanied by histamine-independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, K1.1), a potassium channel highly expressed in itch-sensitive sensory neurons, has therapeutic potential for the treatment of itching.

Efficacy of combined tumor irradiation and K3.1-targeting with TRAM-34 in a syngeneic glioma mouse model.

The intermediate-conductance calcium-activated potassium channel K3.1 has been proposed to be a new potential target for glioblastoma treatment. This study analyzed the effect of combined irradiation and K3.

BK channels sustain neuronal Ca oscillations to support hippocampal long-term potentiation and memory formation.

Mutations of large conductance Ca- and voltage-activated K channels (BK) are associated with cognitive impairment. Here we report that CA1 pyramidal neuron-specific conditional BK knock-out (cKO) mice display normal locomotor and anxiety behavior. They do, however, exhibit impaired memory acquisition and retrieval in the Morris Water Maze (MWM) when compared to littermate controls (CTRL).

Slack K channels limit kainic acid-induced seizure severity in mice by modulating neuronal excitability and firing.

Mutations of the Na-activated K channel Slack (KCNT1) are associated with terrible epilepsy syndromes that already begin in infancy. Here we report increased severity of acute kainic acid-induced seizures in adult and juvenile Slack knockout mice (Slack) in vivo. Fittingly, we find exacerbation of cell death following kainic acid exposure in organotypic hippocampal slices as well as dissociated hippocampal cultures from Slack in vitro.

Tumoricidal, Temozolomide- and Radiation-Sensitizing Effects of K3.1 K Channel Targeting In Vitro Are Dependent on Glioma Cell Line and Stem Cell Fraction.

Reportedly, the intermediate-conductance Ca-activated potassium channel K3.1 contributes to the invasion of glioma cells into healthy brain tissue and resistance to temozolomide and ionizing radiation. Therefore, K3.

IK channels control breast cancer metabolism including AMPK-driven autophagy.

Ca-activated K channels of intermediate conductance (IK) are frequently overexpressed in breast cancer (BC) cells, while IK channel depletion reduces BC cell proliferation and tumorigenesis. This raises the question, of whether and mechanistically how IK activity interferes with the metabolic activity and energy consumption rates, which are fundamental for rapidly growing cells. Using BC cells obtained from MMTV-PyMT tumor-bearing mice, we show that both, glycolysis and mitochondrial ATP-production are reduced in cells derived from IK-deficient breast tumors.

Slack Potassium Channels Modulate TRPA1-Mediated Nociception in Sensory Neurons.

The transient receptor potential (TRP) ankyrin type 1 (TRPA1) channel is highly expressed in a subset of sensory neurons where it acts as an essential detector of painful stimuli. However, the mechanisms that control the activity of sensory neurons upon TRPA1 activation remain poorly understood. Here, using in situ hybridization and immunostaining, we found TRPA1 to be extensively co-localized with the potassium channel Slack (K1.

Cysteine-Rich LIM-Only Protein 4 (CRP4) Promotes Atherogenesis in the ApoE Mouse Model.

Vascular smooth muscle cells (VSMCs) can switch from their contractile state to a synthetic phenotype resulting in high migratory and proliferative capacity and driving atherosclerotic lesion formation. The cysteine-rich LIM-only protein 4 (CRP4) reportedly modulates VSM-like transcriptional signatures, which are perturbed in VSMCs undergoing phenotypic switching. Thus, we hypothesized that CRP4 contributes to adverse VSMC behaviours and thereby to atherogenesis in vivo.

Slick Potassium Channels Control Pain and Itch in Distinct Populations of Sensory and Spinal Neurons in Mice.

Background: Slick, a sodium-activated potassium channel, has been recently identified in somatosensory pathways, but its functional role is poorly understood. The authors of this study hypothesized that Slick is involved in processing sensations of pain and itch.

Methods: Immunostaining, in situ hybridization, Western blot, and real-time quantitative reverse transcription polymerase chain reaction were used to investigate the expression of Slick in dorsal root ganglia and the spinal cord.

Loss of central mineralocorticoid or glucocorticoid receptors impacts auditory nerve processing in the cochlea.

The key auditory signature that may associate peripheral hearing with central auditory cognitive defects remains elusive. Suggesting the involvement of stress receptors, we here deleted the mineralocorticoid and glucocorticoid receptors ( and ) using a CaMKIIα-based tamoxifen-inducible Cre/ approach to generate mice with single or double deletion of central but not cochlear MR and GR. Hearing thresholds of MRGR conditional knockouts () were unchanged, whereas auditory nerve fiber () responses were larger and faster and auditory steady state responses were improved.

Physiological and Pathophysiological Roles of Metabolic Pathways for NET Formation and Other Neutrophil Functions.

Neutrophils are the most numerous cells in the leukocyte population and essential for innate immunity. To limit their effector functions, neutrophils are able to modulate glycolysis and other cellular metabolic pathways. These metabolic pathways are essential not only for energy usage, but also for specialized effector actions, such as the production of reactive oxygen species (ROS), chemotaxis, phagocytosis, degranulation, and the formation of neutrophil extracellular traps (NETs).

Patient-individual phenotypes of glioblastoma stem cells are conserved in culture and associate with radioresistance, brain infiltration and patient prognosis.

Identification of prognostic or predictive molecular markers in glioblastoma resection specimens may lead to strategies for therapy stratification and personalized treatment planning. Here, we analyzed in primary glioblastoma stem cell (pGSC) cultures the mRNA abundances of seven stem cell (MSI1, Notch1, nestin, Sox2, Oct4, FABP7 and ALDH1A3), and three radioresistance or invasion markers (CXCR4, IK and BK ). From these abundances, an mRNA signature was deduced which describes the mesenchymal-to-proneural expression profile of an individual GSC culture.

Can Any Drug Be Repurposed for Cancer Treatment? A Systematic Assessment of the Scientific Literature.

Drug repurposing is a complementary pathway for introducing new drugs against cancer. Broad systematic assessments of ongoing repurposing efforts in oncology are lacking, but may be helpful to critically appraise current and future efforts. Hence, we conducted a systematic PubMed search encompassing 100 frequently prescribed and 100 randomly selected drugs, and assessed the published preclinical anti-cancer effects.

The Na-activated K channel Slack contributes to synaptic development and plasticity.

Human mutations of the Na-activated K channel Slack (KCNT1) are associated with epilepsy and intellectual disability. Accordingly, Slack knockout mice (Slack) exhibit cognitive flexibility deficits in distinct behavioral tasks. So far, however, the underlying causes as well as the role of Slack in hippocampus-dependent memory functions remain enigmatic.

Cyclic GMP-Dependent Regulation of Vascular Tone and Blood Pressure Involves Cysteine-Rich LIM-Only Protein 4 (CRP4).

The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric oxide (NO)-induced cGMP signaling through cGMP-dependent protein kinase type I (cGKI) play fundamental roles in the physiological regulation of vascular tone and arterial blood pressure (BP). However, it remains unclear whether the vasorelaxant actions attributed to the NO/cGMP axis require CRP4.

Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing.

The sodium-activated potassium channel Slack (K1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (I) and modulates neuronal activity.

Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia: A Preclinical Investigation.

Reduced Cl conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca- and voltage-activated K channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia.