VU0606170, a Selective Slack Channels Inhibitor, Decreases Calcium Oscillations in Cultured Cortical Neurons.

Malignant migrating partial seizures of infancy is a rare, devastating form of epilepsy most commonly associated with gain-of-function mutations in the potassium channel, Slack. Not only is this condition almost completely pharmacoresistant, there are not even selective drug-like tools available to evaluate whether inhibition of these overactivated, mutant Slack channels may represent a viable path forward toward new antiepileptic therapies. Therefore, we used a high-throughput thallium flux assay to screen a drug-like, 100 000-compound library in search of inhibitors of both wild-type and a disease-associated mutant Slack channel.

Functional Coupling of K-Cl Cotransporter (KCC) to GABA-Gated Cl Channels in the Central Nervous System of Drosophila melanogaster Leads to Altered Drug Sensitivities.

GABAergic signaling is the cornerstone for fast synaptic inhibition of neural signaling in arthropods and mammals and is the molecular target for insecticides and pharmaceuticals, respectively. The K-Cl cotransporter (KCC) is the primary mechanism by which mature neurons maintain low intracellular Cl concentration, yet the fundamental physiology, comparative physiology, and toxicological relevance of insect KCC is understudied. Considering this, we employed electrophysiological, genetic, and pharmacological methods to characterize the physiological underpinnings of KCC function to the Drosophila CNS.

Use of chemical probes to explore the toxicological potential of the K/Cl cotransporter (KCC) as a novel insecticide target to control the primary vector of dengue and Zika virus, Aedes aegypti.

The majority of commercialized insecticides target the insect nervous system and therefore, neural proteins are well-validated targets for insecticide development. Considering that only a few neural targets are exploited for insecticidal action and the development of insecticide resistance has reduced the efficacy of current insecticidal classes, we sought to test the toxicological potential of the potassium-chloride cotransporter (KCC). In mammals, KCC proteins have seminal roles in shaping GABAergic signaling and inhibitory neurotransmission, thus ion transport through KCC is critical for proper neurotransmission.

Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-Gated, Inwardly Rectifying, Potassium (GIRK) Channels.

G protein-gated, inwardly rectifying, potassium (GIRK) channels are important regulators of cellular excitability throughout the body. GIRK channels are heterotetrameric and homotetrameric combinations of the K3.1-4 (GIRK1-4) subunits.