The antioxidant property of CAPE depends on TRPV1 channel activation in microvascular endothelial cells.

Caffeic acid phenethyl ester (CAPE) is a hydrophobic phytochemical typically found in propolis that acts as an antioxidant, anti-inflammatory and cardiovascular protector, among several other properties. However, the molecular entity responsible for recognising CAPE is unknown, and whether that molecular interaction is involved in developing an antioxidant response in the target cells remains an unanswered question. Herein, we hypothesized that a subfamily of TRP ion channels works as the molecular entity that recognizes CAPE at the plasma membrane and allows a fast shift in the antioxidant capacity of intact endothelial cells (EC).

K-Driven Cl/HCO Exchange Mediated by Slc4a8 and Slc4a10.

Slc4a genes encode various types of transporters, including Na-HCO cotransporters, Cl/HCO exchangers, or Na-driven Cl/HCO exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl/HCO exchanger, which can be driven by either Na or K, prompting investigation into whether other Slc4a members facilitate cation-dependent anion transport. In the present study, we show that either Na or K drive Cl/HCO exchanger activity in cells overexpressing Slc4a8 or Slc4a10.

Selective TASK-1 Inhibitor with a Defined Structure-Activity Relationship Reduces Cancer Cell Proliferation and Viability.

Chemical structures of selective blockers of TASK channels contain aromatic groups and amide bonds. Using this rationale, we designed and synthesized a series of compounds based on 3-benzamidobenzoic acid. These compounds block TASK-1 channels by binding to the central cavity.

Potassium Channels as a Target for Cancer Therapy: Current Perspectives.

Potassium (K) channels are highly regulated membrane proteins that control the potassium ion flux and respond to different cellular stimuli. These ion channels are grouped into three major families, Kv (voltage-gated K channel), Kir (inwardly rectifying K channel) and K2P (two-pore K channels), according to the structure, to mediate the K currents. In cancer, alterations in K channel function can promote the acquisition of the so-called hallmarks of cancer - cell proliferation, resistance to apoptosis, metabolic changes, angiogenesis, and migratory capabilities - emerging as targets for the development of new therapeutic drugs.

A Direct Interaction between Cyclodextrins and TASK Channels Decreases the Leak Current in Cerebellar Granule Neurons.

Two pore domain potassium channels (K2P) are strongly expressed in the nervous system (CNS), where they play a central role in excitability. These channels give rise to background K currents, also known as IK (standing-outward potassium current). We detected the expression in primary cultured cerebellar granule neurons (CGNs) of TWIK-1 (K2P1), TASK-1 (K2P3), TASK-3 (K2P9), and TRESK (K2P18) channels by immunocytochemistry and their association with lipid rafts using the specific lipids raft markers flotillin-2 and caveolin-1.

Common Structural Pattern for Flecainide Binding in Atrial-Selective K1.5 and Na1.5 Channels: A Computational Approach.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy.

Withaferin A suppresses breast cancer cell proliferation by inhibition of the two-pore domain potassium (K2P9) channel TASK-3.

Withaferin A (WFA), a C,C-epoxy steroidal lactone isolated from the medicinal plant Withania somnifera (L.) Dunal, inhibits growth of tumor cells in different cancer types. However, the mechanisms underlying the effect of WFA on tumor cells are not fully understood.

Elucidating the Structural Basis of the Intracellular pH Sensing Mechanism of TASK-2 KP Channels.

Two-pore domain potassium (KP) channels maintain the cell's background conductance by stabilizing the resting membrane potential. They assemble as dimers possessing four transmembrane helices in each subunit. KP channels were crystallized in "up" and "down" states.

Gene Knockdown Dampens Invasion and Migration and Promotes Apoptosis in KATO III and MKN-45 Human Gastric Adenocarcinoma Cell Lines.

Incidence and mortality of gastric cancer is increasing worldwide, in part, because of the lack of new therapeutic targets to treat this disease. Different types of ion channels participate in the hallmarks of cancer. In this context, ion channels are known to exert control over the cell cycle, mechanisms that support survival, angiogenesis, migration, and cell invasion.

Correction: Concha, G., et al. The Insensitivity of TASK-3 KP Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure. 2018, , 2437.

We would like to submit the following correction to our published paper [...

Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening.

TASK-3 is a two-pore domain potassium (K) channel highly expressed in the hippocampus, cerebellum, and cortex. TASK-3 has been identified as an oncogenic potassium channel and it is overexpressed in different cancer types. For this reason, the development of new TASK-3 blockers could influence the pharmacological treatment of cancer and several neurological conditions.

HCN Channels: New Therapeutic Targets for Pain Treatment.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are highly regulated proteins which respond to different cellular stimuli. The HCN currents (I) mediated by HCN1 and HCN2 drive the repetitive firing in nociceptive neurons. The role of HCN channels in pain has been widely investigated as targets for the development of new therapeutic drugs, but the comprehensive design of HCN channel modulators has been restricted due to the lack of crystallographic data.

The Insensitivity of TASK-3 K₂P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure.

Two-pore domain K⁺ channels (K₂P) display a characteristic extracellular cap structure formed by two M1-P1 linkers, the functional role of which is poorly understood. It has been proposed that the presence of the cap explains the insensitivity of K₂P channels to several K⁺ channel blockers including tetraethylammonium (TEA). We have explored this hypothesis using mutagenesis and functional analysis, followed by molecular simulations.

TASK-3 Downregulation Triggers Cellular Senescence and Growth Inhibition in Breast Cancer Cell Lines.

TASK-3 potassium channels are believed to promote proliferation and survival of cancer cells, in part, by augmenting their resistance to both hypoxia and serum deprivation. While overexpression of TASK-3 is frequently observed in cancers, the understanding of its role and regulation during tumorigenesis remains incomplete. Here, we evaluated the effect of reducing the expression of TASK-3 in MDA-MB-231 and MCF-10F human mammary epithelial cell lines through small hairpin RNA (shRNA)-mediated knockdown.

Insulin Induces Relaxation and Decreases Hydrogen Peroxide-Induced Vasoconstriction in Human Placental Vascular Bed in a Mechanism Mediated by Calcium-Activated Potassium Channels and L-Arginine/Nitric Oxide Pathways.

Short-term incubation with insulin increases the L-arginine transport in HUVECs.Short-term incubation with insulin increases the NO synthesis in HUVECs.Insulin induces relaxation in human placental vascular bed.

Expression and cellular localization of HCN channels in rat cerebellar granule neurons.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated pore loop channels. In mammals, this family consists of four different subunits (HCN1-4) and their ion channels activity have been proposed to play an essential role in regulating the membrane potential of excitable cells. Here, we describe the expression and relative abundances of HCN channels in cerebellum and primary cultures of cerebellar granule neurons (CGN).

Cardiovascular Action of Insulin in Health and Disease: Endothelial L-Arginine Transport and Cardiac Voltage-Dependent Potassium Channels.

Impairment of insulin signaling on diabetes mellitus has been related to cardiovascular dysfunction, heart failure, and sudden death. In human endothelium, cationic amino acid transporter 1 (hCAT-1) is related to the synthesis of nitric oxide (NO) and insulin has a vascular effect in endothelial cells through a signaling pathway that involves increases in hCAT-1 expression and L-arginine transport. This mechanism is disrupted in diabetes, a phenomenon potentiated by excessive accumulation of reactive oxygen species (ROS), which contribute to lower availability of NO and endothelial dysfunction.

K₂p channels in plants and animals.

Two-pore domain potassium (K2P) channels are membrane proteins widely identified in mammals, plants, and other organisms. A functional channel is a dimer with each subunit comprising two pore-forming loops and four transmembrane domains. The genome of the model plant Arabidopsis thaliana harbors five genes coding for K2P channels.

Differential expression of two-pore domain potassium channels in rat cerebellar granule neurons.

Two pore domain potassium (K2P) channels are mostly present in the central nervous system (CNS) where they play important roles in modulating neuronal excitability. K2P channels give rise to background K(+) currents (IKSO) a key component in setting and maintaining the resting membrane potential in excitable cells. Here, we studied the expression and relative abundances of K2P channels in cerebellar granule neurons (CGNs), combining molecular biology, electrophysiology and immunologic techniques.

An extracellular ion pathway plays a central role in the cooperative gating of a K(2P) K+ channel by extracellular pH.

Proton-gated TASK-3 K(+) channel belongs to the K(2P) family of proteins that underlie the K(+) leak setting the membrane potential in all cells. TASK-3 is under cooperative gating control by extracellular [H(+)]. Use of recently solved K(2P) structures allows us to explore the molecular mechanism of TASK-3 cooperative pH gating.

SUMOylation silences heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule neurons.

The standing outward K(+) current (IKso) governs the response of cerebellar granule neurons to natural and medicinal stimuli including volatile anesthetics. We showed that SUMOylation silenced half of IKso at the surface of cerebellar granule neurons because the underlying channels were heterodimeric assemblies of K2P1, a subunit subject to SUMOylation, and the TASK (two-P domain, acid-sensitive K(+)) channel subunits K2P3 or K2P9. The heterodimeric channels comprised the acid-sensitive portion of IKso and mediated its response to halothane.

Gating of a pH-sensitive K(2P) potassium channel by an electrostatic effect of basic sensor residues on the selectivity filter.

K(+) channels share common selectivity characteristics but exhibit a wide diversity in how they are gated open. Leak K(2P) K(+) channels TASK-2, TALK-1 and TALK-2 are gated open by extracellular alkalinization. The mechanism for this alkalinization-dependent gating has been proposed to be the neutralization of the side chain of a single arginine (lysine in TALK-2) residue near the pore of TASK-2, which occurs with the unusual pK(a) of 8.

Rapid recycling of ClC-2 chloride channels between plasma membrane and endosomes: role of a tyrosine endocytosis motif in surface retrieval.

ClC-2 chloride channel is present in the brain and some transporting epithelia where its function is poorly understood. We have now demonstrated that the surface channels are rapidly internalised and approximately the 70% of the surface membrane protein recycles after 4- to 8-min internalisation. Endocytosis of ClC-2 was dependent upon tyrosine 179 located within an endocytic motif.

Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel.

Potassium channels share a common selectivity filter that determines the conduction characteristics of the pore. Diversity in K+ channels is given by how they are gated open. TASK-2, TALK-1, and TALK-2 are two-pore region (2P) KCNK K+ channels gated open by extracellular alkalinization.