Ancillary subunits KChIP2c and DPP6 differentially modulate the inhibition of Kv4.2 channels by riluzole.

In native tissue, Kv4.2 channels associate with the ancillary subunits Kv channels interacting proteins (KChIPs) and dipeptidyl peptidase-related proteins (DPPs) to evoke rapidly activating/inactivating currents in the heart (I) and brain (I). Despite extensive knowledge of Kv4.

Vasorelaxant Effect and Blood Pressure Reduction Potential of Pitaya Juice Concentrate () Associated with Calcium Channel Blockade.

Arterial hypertension is a highly prevalent chronic disease worldwide, with several etiologies and treatments that may eventually have side effects or result in patients developing tolerance. There is growing interest in traditional medicine and functional foods to isolate biomolecules that could be useful as coadjuvants for treating several aliments. Pitaya, a desert fruit endemic in Mexico, is a rich source of bioactive molecules (betalains and phenolic compounds).

Inhibition of Kv2.1 potassium channels by the antidepressant drug sertraline.

Sertraline is a commonly used antidepressant of the selective serotonin reuptake inhibitors (SSRIs) class. In this study, we have used the patch-clamp technique to assess the effects of sertraline on Kv2.1 channels heterologously expressed in HEK-293 cells and on the voltage-gated potassium currents (I) of Neuro 2a cells, which are predominantly mediated by Kv2.

Crosstalk between cholesterol and PIP in the regulation of Kv7.2/Kv7.3 channels.

The activity of neuronal Kv7.2/Kv7.3 channels is critically dependent on PIP and finely modulated by cholesterol.

Phosphatidylinositol 4,5-Bisphosphate and Cholesterol Regulators of the Calcium-Activated Chloride Channels TMEM16A and TMEM16B.

Chloride fluxes through homo-dimeric calcium-activated channels TMEM16A and TMEM16B are critical to blood pressure, gastrointestinal motility, hormone, fluid and electrolyte secretion, pain sensation, sensory transduction, and neuronal and muscle excitability. Their gating depends on the voltage-dependent binding of two intracellular calcium ions to a high-affinity site formed by acidic residues from α-helices 6-8 in each monomer. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a low-abundant lipid of the inner leaflet, supports TMEM16A function; it allows TMEM16A to evade the down-regulation induced by calcium, poly-L-lysine, or PI(4,5)P2 5-phosphatase.

Determination of the size of lipid rafts studied through single-molecule FRET simulations.

Fluorescence resonance energy transfer (FRET) is a high-resolution technique that allows the characterization of spatial and temporal properties of biological structures and mechanisms. In this work, we developed an in silico single-molecule FRET methodology to study the dynamics of fluorophores inside lipid rafts. We monitored the fluorescence of a single acceptor molecule in the presence of several donor molecules.

Kir4.1/Kir5.1 channels possess strong intrinsic inward rectification determined by a voltage-dependent K+-flux gating mechanism.

Inwardly rectifying potassium (Kir) channels are broadly expressed in both excitable and nonexcitable tissues, where they contribute to a wide variety of cellular functions. Numerous studies have established that rectification of Kir channels is not an inherent property of the channel protein itself, but rather reflects strong voltage dependence of channel block by intracellular cations, such as polyamines and Mg2+. Here, we identify a previously unknown mechanism of inward rectification in Kir4.

Riluzole inhibits Kv4.2 channels acting on the closed and closed inactivated states.

Riluzole is an anticonvulsant drug also used to treat the amyotrophic lateral sclerosis and major depressive disorder. This compound has antiglutamatergic activity and is an important multichannel blocker. However, little is known about its actions on the Kv4.

Inhibitory effect of terfenadine on Kir2.1 and Kir2.3 channels.

Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer properties. Lately, the subfamily 2 of inward rectifier potassium channels (Kir2) has been implicated in the progression of some tumoral processes. Hence, we characterized the effects of terfenadine on Kir2.

In vitro and in silico characterization of the inhibition of Kir4.1 channels by aminoglycoside antibiotics.

Background And Purpose: Aminoglycoside antibiotics are positively charged molecules that are known to inhibit several ion channels. In this study, we have shown that aminoglycosides also inhibit the activity of Kir4.1 channels.

Voltage-induced structural modifications on M2 muscarinic receptor and their functional implications when interacting with the superagonist iperoxo.

It has been reported that muscarinic type-2 receptors (M2R) are voltage sensitive in an agonist-specific manner. In this work, we studied the effects of membrane potential on the interaction of M2R with the superagonist iperoxo (IXO), both functionally (using the activation of the ACh-gated K current (I) in cardiomyocytes) and by molecular dynamics (MD) simulations. We found that IXO activated I with remarkable high potency and clear voltage dependence, displaying a larger effect at the hyperpolarized potential.

Functional marriage in plasma membrane: Critical cholesterol level-optimal protein activity.

In physiology, homeostasis refers to the condition where a system exhibits an optimum functional level. In contrast, any variation from this optimum is considered as a dysfunctional or pathological state. In this review, we address the proposal that a critical cholesterol level in the plasma membrane is required for the proper functioning of transmembrane proteins.

Chloroquine inhibits tumor-related Kv10.1 channel and decreases migration of MDA-MB-231 breast cancer cells in vitro.

Chloroquine (CQ) is an old antimalarial drug currently being investigated for its anti-tumor properties. As chloroquine has been shown to inhibits several potassium channels, we decided to study its effect on the tumor-related Kv10.1 channel by using patch-clamp electrophysiology and cell migration assays.

Cytoskeleton disruption affects Kv2.1 channel function and its modulation by PIP.

Voltage-gated potassium channels are expressed in a wide variety of excitable and non-excitable cells and regulate numerous cellular functions. The activity of ion channels can be modulated by direct interaction or/and functional coupling with other proteins including auxiliary subunits, scaffold proteins and the cytoskeleton. Here, we evaluated the influence of the actin-based cytoskeleton on the Kv2.

Dual regulation of hEAG1 channels by phosphatidylinositol 4,5-bisphosphate.

The ether-à-go-go1 (EAG1, Kv10.1) K channel is a member of the voltage-gated K channel family mainly expressed in the central nervous system and cancer cells. Membrane lipids regulate several voltage-gated K channels but their influence on EAG1 channels has been poorly explored.

Regulation of Kv7.2/Kv7.3 channels by cholesterol: Relevance of an optimum plasma membrane cholesterol content.

Kv7.2/Kv7.3 channels are the molecular correlate of the M-current, which stabilizes the membrane potential and controls neuronal excitability.

Regulation of Kv2.1 channel inactivation by phosphatidylinositol 4,5-bisphosphate.

Phosphatidylinositol 4,5-bisphosphate (PIP) is a membrane phospholipid that regulates the function of multiple ion channels, including some members of the voltage-gated potassium (Kv) channel superfamily. The PIP sensitivity of Kv channels is well established for all five members of the Kv7 family and for Kv1.2 channels; however, regulation of other Kv channels by PIP remains unclear.

Phytochemicals genistein and capsaicin modulate Kv2.1 channel gating.

Background: Phytochemicals are a large group of plant-derived compounds that have a broad range of pharmacological effects. Some of these effects are derived from their action on transport proteins, including ion channels. The present study investigates the effects of the phytochemicals genistein and capsaicin on voltage-gated potassium Kv2.

High-potency block of Kir4.1 channels by pentamidine: Molecular basis.

Inward rectifier potassium (Kir) channels are expressed in almost all mammalian tissues and contribute to a wide range of physiological processes. Kir4.1 channel expression is found in the brain, inner ear, eye, and kidney.

Inhibition of Kir4.1 potassium channels by quinacrine.

Inwardly rectifying potassium (Kir) channels are expressed in many cell types and contribute to a wide range of physiological processes. Particularly, Kir4.1 channels are involved in the astroglial spatial potassium buffering.

Chloroquine blocks the Kir4.1 channels by an open-pore blocking mechanism.

Kir4.1 channels have been implicated in various physiological processes, mainly in the K homeostasis of the central nervous system and in the control of glial function and neuronal excitability. Even though, pharmacological research of these channels is very limited.

Extracellular protons enable activation of the calcium-dependent chloride channel TMEM16A.

Key Points: The calcium-activated chloride channel TMEM16A provides a pathway for chloride ion movements that are key in preventing polyspermy, allowing fluid secretion, controlling blood pressure, and enabling gastrointestinal activity. TMEM16A is opened by voltage-dependent calcium binding and regulated by permeant anions and intracellular protons. Here we show that a low proton concentration reduces TMEM16A activity while maximum activation is obtained when the external proton concentration is high.

Revealing the activation pathway for TMEM16A chloride channels from macroscopic currents and kinetic models.

TMEM16A (ANO1), the pore-forming subunit of calcium-activated chloride channels, regulates several physiological and pathophysiological processes such as smooth muscle contraction, cardiac and neuronal excitability, salivary secretion, tumour growth and cancer progression. Gating of TMEM16A is complex because it involves the interplay between increases in intracellular calcium concentration ([Ca(2+)]i), membrane depolarization, extracellular Cl(-) or permeant anions and intracellular protons. Our goal here was to understand how these variables regulate TMEM16A gating and to explain four observations.

Modulation of the voltage-gated potassium channel Kv2.1 by the anti-tumor alkylphospholipid perifosine.

Background: The aim of the present study was to assess the effects of perifosine-a third generation alkylphospholipid analog with anti-tumor properties-on the activity of Kv2.1 channels.

Methods: The whole-cell patch clamp technique was applied to follow the modulatory effect of perifosine on Kv2.

The molecular basis of chloroethylclonidine block of inward rectifier (Kir2.1 and Kir4.1) K(+) channels.

Background: Inwardly rectifying potassium (Kir) channels are expressed in many cell types and contribute to a wide range of physiological processes. Kir channels dysfunction cause several diseases in brain, ear, heart, muscle, kidney and pancreas, and developmental abnormalities. Therefore, a better understanding of Kir channels pharmacology is desirable.