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Pflugers Archiv : European Journal of... Jul 2022KCNQ channels participate in the physiology of several cell types. In neurons of the central nervous system, the primary subunits are KCNQ2, 3, and 5. Activation of...
KCNQ channels participate in the physiology of several cell types. In neurons of the central nervous system, the primary subunits are KCNQ2, 3, and 5. Activation of these channels silence the neurons, limiting action potential duration and preventing high-frequency action potential burst. Loss-of-function mutations of the KCNQ channels are associated with a wide spectrum of phenotypes characterized by hyperexcitability. Hence, pharmacological activation of these channels is an attractive strategy to treat epilepsy and other hyperexcitability conditions as are the evolution of stroke and traumatic brain injury. In this work we show that triclosan, a bactericide widely used in personal care products, activates the KCNQ3 channels but not the KCNQ2. Triclosan induces a voltage shift in the activation, increases the conductance, and slows the closing of the channel. The response is independent of PIP. Molecular docking simulations together with site-directed mutagenesis suggest that the putative binding site is in the voltage sensor domain. Our results indicate that triclosan is a new activator for KCNQ channels.
Topics: Epilepsy; Humans; KCNQ Potassium Channels; KCNQ1 Potassium Channel; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Molecular Docking Simulation; Neurotransmitter Agents; Triclosan
PubMed: 35459955
DOI: 10.1007/s00424-022-02692-w -
Journal of Medicinal Chemistry Nov 2019Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the... (Review)
Review
Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the wild chemical space and unravel the molecular basis of the ion channels modulators binding mechanisms. TASK channels belong to the two-pore domain potassium channel family and are modulated by extracellular acidosis. They are extensively distributed along the cardiovascular and central nervous systems, and their expression is up- and downregulated in different cancer types, which makes them an attractive therapeutic target. However, TASK channels remain unexplored, and drugs designed to target these channels are poorly selective. Here, we review TASK channels properties and their known blockers and activators, considering the new challenges in ion channels drug design and focusing on the implementation of computational methodologies in the drug discovery process.
Topics: Animals; Drug Design; Drug Discovery; Humans; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Tandem Pore Domain
PubMed: 31260312
DOI: 10.1021/acs.jmedchem.9b00248 -
ELife Mar 2017Electron cryo-microscopy has revealed the three-dimensional structure of a potassium channel that has a central role in regulating the release of insulin from the...
Electron cryo-microscopy has revealed the three-dimensional structure of a potassium channel that has a central role in regulating the release of insulin from the pancreas.
Topics: Adenosine Triphosphate; Cryoelectron Microscopy; Insulin; Ions; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors
PubMed: 28276322
DOI: 10.7554/eLife.25159 -
Arteriosclerosis, Thrombosis, and... Sep 2014Perivascular adipose tissue has been recognized unequivocally as a major player in the pathology of metabolic and cardiovascular diseases. Through its production of... (Review)
Review
Perivascular adipose tissue has been recognized unequivocally as a major player in the pathology of metabolic and cardiovascular diseases. Through its production of adipokines and the release of other thus far unidentified factors, this recently discovered adipose tissue modulates vascular regulation and the myogenic response. After the discovery of its ability to diminish the vessel's response to vasoconstrictors, a new paradigm established adipose-derived relaxing factor (ADRF) as a paracrine smooth muscle cells' potassium channel opener that could potentially help combat vascular dysfunction. This review will discuss the role of ADRF in vascular dysfunction in obesity and hypertension, the different potassium channels that can be activated by this factor, and describes new pharmacological tools that can mimic the ADRF effect and thus can be beneficial against vascular dysfunction in cardiovascular disease.
Topics: Adipokines; Adipose Tissue; Animals; Biological Factors; Blood Vessels; Cardiovascular Diseases; Endothelium, Vascular; Humans; Hypertension; KCNQ Potassium Channels; Muscle Contraction; Muscle, Smooth, Vascular; Obesity; Potassium Channel Blockers; Potassium Channels; Vasoconstrictor Agents
PubMed: 25012133
DOI: 10.1161/ATVBAHA.114.303032 -
Current Medicinal Chemistry 2019Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function,... (Review)
Review
BACKGROUND
Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function, hormone secretion, osmotic pressure, changes in gene expression, and are involved in critical biological functions, and in a variety of diseases. Potassium channels represent a large family of tetrameric membrane proteins. Potassium channels activation reduces excitability, whereas channel inhibition increases excitability.
OBJECTIVE
Small molecule K+ channel activators and inhibitors interact with voltage-gated, inward rectifying, and two-pore tandem potassium channels. Due to their involvement in biological functions, and in a variety of diseases, small molecules as potassium channel modulators have received great scientific attention.
METHODS
In this review, we have compiled the literature, patents and patent applications (2011 to 2017) related to different chemical classes of potassium channel openers and blockers as therapeutic agents for the treatment of various diseases. Many different chemical classes of selective small molecule have emerged as potassium channel modulators over the past years.
CONCLUSION
This review discussed the current understanding of medicinal chemistry research in the field of potassium channel modulators to update the key advances in this field.
Topics: Benzopyrans; Benzothiazoles; Chemistry, Pharmaceutical; Humans; Patents as Topic; Potassium Channel Blockers; Potassium Channels; Pyrazoles; Pyrimidines; Small Molecule Libraries
PubMed: 29714134
DOI: 10.2174/0929867325666180430152023 -
Journal of Cardiovascular Pharmacology... Mar 2018The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and... (Review)
Review
The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes potential cardiac and extracardiac toxicity. Of these, K channels contribute numerous and diverse currents with specific actions on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular K channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a number of available potential antiarrhythmic drugs directed at them.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Drug Development; Heart; Heart Diseases; Heart Rate; Humans; Molecular Targeted Therapy; Myocytes, Cardiac; Potassium Channel Blockers; Potassium Channels
PubMed: 28946759
DOI: 10.1177/1074248417729880 -
Developmental Neuroscience 2021KCNQ2 and KCNQ3 pathogenic channel variants have been associated with a spectrum of developmentally regulated diseases that vary in age of onset, severity, and whether... (Review)
Review
KCNQ2 and KCNQ3 pathogenic channel variants have been associated with a spectrum of developmentally regulated diseases that vary in age of onset, severity, and whether it is transient (i.e., benign familial neonatal seizures) or long-lasting (i.e., developmental and epileptic encephalopathy). KCNQ2 and KCNQ3 channels have also emerged as a target for novel antiepileptic drugs as their activation could reduce epileptic activity. Consequently, a great effort has taken place over the last 2 decades to understand the mechanisms that control the assembly, gating, and modulation of KCNQ2 and KCNQ3 channels. The current view that KCNQ2 and KCNQ3 channels assemble as heteromeric channels (KCNQ2/3) forms the basis of our understanding of KCNQ2 and KCNQ3 channelopathies and drug design. Here, we review the evidence that supports the formation of KCNQ2/3 heteromers in neurons. We also highlight functional and transcriptomic studies that suggest channel composition might not be necessarily fixed in the nervous system, but rather is dynamic and flexible, allowing some neurons to express KCNQ2 and KCNQ3 homomers. We propose that to fully understand KCNQ2 and KCNQ3 channelopathies, we need to adopt a more flexible view of KCNQ2 and KCNQ3 channel stoichiometry, which might differ across development, brain regions, cell types, and disease states.
Topics: Epilepsy; Epilepsy, Benign Neonatal; Humans; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Neurodevelopmental Disorders
PubMed: 33794528
DOI: 10.1159/000515495 -
Current Opinion in Nephrology and... Sep 2018Multiple clinical and translational evidence support benefits of high potassium diet; however, there many uncertainties underlying the molecular and cellular mechanisms... (Review)
Review
PURPOSE OF REVIEW
Multiple clinical and translational evidence support benefits of high potassium diet; however, there many uncertainties underlying the molecular and cellular mechanisms determining effects of dietary potassium. Kir4.1 and Kir5.1 proteins form a functional heteromer (Kir4.1/Kir5.1), which is the primary inwardly rectifying potassium channel on the basolateral membrane of both distal convoluted tubule (DCT) and the collecting duct principal cells. The purpose of this mini-review is to summarize latest advances in our understanding of the evolution, physiological relevance and mechanisms controlling these channels.
RECENT FINDINGS
Kir4.1 and Kir5.1 channels play a critical role in determining electrolyte homeostasis in the kidney and blood pressure, respectively. It was reported that Kir4.1/Kir5.1 serves as potassium sensors in the distal nephron responding to variations in dietary intake and hormonal stimuli. Global and kidney specific knockouts of either channel resulted in hypokalemia and severe cardiorenal phenotypes. Furthermore, knock out of Kir5.1 in Dahl salt-sensitive rat background revealed the crucial role of the Kir4.1/Kir5.1 channel in salt-induced hypertension.
SUMMARY
Here, we focus on reviewing novel experimental evidence of the physiological function, expression and hormonal regulation of renal basolateral inwardly rectifying potassium channels. Further investigation of molecular and cellular mechanisms controlling Kir4.1 and Kir4.1/Kir5.1-mediating pathways and development of specific compounds targeting these channels function is essential for proper control of electrolyte homeostasis and blood pressure.
Topics: Animals; Blood Pressure; Humans; Kidney Tubules, Collecting; Kidney Tubules, Distal; Potassium; Potassium Channels; Potassium Channels, Inwardly Rectifying; Potassium, Dietary; Rats; Sodium; Sodium, Dietary; Water-Electrolyte Balance; Kir5.1 Channel
PubMed: 29894319
DOI: 10.1097/MNH.0000000000000437 -
Scientific Reports Jul 2021The voltage-dependent potassium channel Kv1.3 participates in the immune response. Kv1.3 is essential in different cellular functions, such as proliferation, activation...
The voltage-dependent potassium channel Kv1.3 participates in the immune response. Kv1.3 is essential in different cellular functions, such as proliferation, activation and apoptosis. Because aberrant expression of Kv1.3 is linked to autoimmune diseases, fine-tuning its function is crucial for leukocyte physiology. Regulatory KCNE subunits are expressed in the immune system, and KCNE4 specifically tightly regulates Kv1.3. KCNE4 modulates Kv1.3 currents slowing activation, accelerating inactivation and retaining the channel at the endoplasmic reticulum (ER), thereby altering its membrane localization. In addition, KCNE4 genomic variants are associated with immune pathologies. Therefore, an in-depth knowledge of KCNE4 function is extremely relevant for understanding immune system physiology. We demonstrate that KCNE4 dimerizes, which is unique among KCNE regulatory peptide family members. Furthermore, the juxtamembrane tetraleucine carboxyl-terminal domain of KCNE4 is a structural platform in which Kv1.3, Ca/calmodulin (CaM) and dimerizing KCNE4 compete for multiple interaction partners. CaM-dependent KCNE4 dimerization controls KCNE4 membrane targeting and modulates its interaction with Kv1.3. KCNE4, which is highly retained at the ER, contains an important ER retention motif near the tetraleucine motif. Upon escaping the ER in a CaM-dependent pattern, KCNE4 follows a COP-II-dependent forward trafficking mechanism. Therefore, CaM, an essential signaling molecule that controls the dimerization and membrane targeting of KCNE4, modulates the KCNE4-dependent regulation of Kv1.3, which in turn fine-tunes leukocyte physiology.
Topics: Amino Acid Motifs; Amino Acid Sequence; Animals; Calmodulin; Cell Membrane; Electrophysiological Phenomena; Gene Expression; HEK293 Cells; Humans; Ion Channel Gating; Kv1.3 Potassium Channel; Leukocytes; Models, Biological; Organ Specificity; Potassium Channels, Voltage-Gated; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization
PubMed: 34234241
DOI: 10.1038/s41598-021-93562-5 -
The Journal of Biological Chemistry Aug 2020Two-pore-domain potassium channels (K) are the major determinants of the background potassium conductance. They play a crucial role in setting the resting membrane...
Two-pore-domain potassium channels (K) are the major determinants of the background potassium conductance. They play a crucial role in setting the resting membrane potential and regulating cellular excitability. These channels form homodimers; however, a few examples of heterodimerization have also been reported. The K channel subunits TRESK and TREK-2 provide the predominant background potassium current in the primary sensory neurons of the dorsal root and trigeminal ganglia. A recent study has shown that a TRESK mutation causes migraine because it leads to the formation of a dominant negative truncated TRESK fragment. Surprisingly, this fragment can also interact with TREK-2. In this study, we determined the biophysical and pharmacological properties of the TRESK/TREK-2 heterodimer using a covalently linked TRESK/TREK-2 construct to ensure the assembly of the different subunits. The tandem channel has an intermediate single-channel conductance compared with the TRESK and TREK-2 homodimers. Similar conductance values were recorded when TRESK and TREK-2 were coexpressed, demonstrating that the two subunits can spontaneously form functional heterodimers. The TRESK component confers calcineurin-dependent regulation to the heterodimer and gives rise to a pharmacological profile similar to the TRESK homodimer, whereas the presence of the TREK-2 subunit renders the channel sensitive to the selective TREK-2 activator T2A3. In trigeminal primary sensory neurons, we detected single-channel activity with biophysical and pharmacological properties similar to the TRESK/TREK-2 tandem, indicating that WT TRESK and TREK-2 subunits coassemble to form functional heterodimeric channels also in native cells.
Topics: Animals; HEK293 Cells; Humans; Ion Transport; Mice; Neurons; Potassium; Potassium Channels; Potassium Channels, Tandem Pore Domain; Protein Multimerization; Somatosensory Cortex; Xenopus laevis
PubMed: 32641496
DOI: 10.1074/jbc.RA120.014125