0
selected
-
1.
The Persistent Question of Potassium Channel Permeation Mechanisms.
Mironenko, A, Zachariae, U, de Groot, BL, Kopec, W
Journal of molecular biology. 2021;(17):167002
Abstract
Potassium channels play critical roles in many physiological processes, providing a selective permeation route for K+ ions in and out of a cell, by employing a carefully designed selectivity filter, evolutionarily conserved from viruses to mammals. The structure of the selectivity filter was determined at atomic resolution by x-ray crystallography, showing a tight coordination of desolvated K+ ions by the channel. However, the molecular mechanism of K+ ions permeation through potassium channels remains unclear, with structural, functional and computational studies often providing conflicting data and interpretations. In this review, we will present the proposed mechanisms, discuss their origins, and will critically assess them against all available data. General properties shared by all potassium channels are introduced first, followed by the introduction of two main mechanisms of ion permeation: soft and direct knock-on. Then, we will discuss critical computational and experimental studies that shaped the field. We will especially focus on molecular dynamics (MD) simulations, that provided mechanistic and energetic aspects of K+ permeation, but at the same time created long-standing controversies. Further challenges and possible solutions are presented as well.
-
2.
From Bench to Biomolecular Simulation: Phospholipid Modulation of Potassium Channels.
Pipatpolkai, T, Quetschlich, D, Stansfeld, PJ
Journal of molecular biology. 2021;(17):167105
Abstract
Potassium (K+) ion channels are crucial in numerous cellular processes as they hyperpolarise a cell through K+ conductance, returning a cell to its resting potential. K+ channel mutations result in multiple clinical complications such as arrhythmia, neonatal diabetes and migraines. Since 1995, the regulation of K+ channels by phospholipids has been heavily studied using a range of interdisciplinary methods such as cellular electrophysiology, structural biology and computational modelling. As a result, K+ channels are model proteins for the analysis of protein-lipid interactions. In this review, we will focus on the roles of lipids in the regulation of K+ channels, and how atomic-level structures, along with experimental techniques and molecular simulations, have helped guide our understanding of the importance of phospholipid interactions.
-
3.
Clinical Importance of the Human Umbilical Artery Potassium Channels.
Lorigo, M, Oliveira, N, Cairrao, E
Cells. 2020;(9)
Abstract
Potassium (K+) channels are usually predominant in the membranes of vascular smooth muscle cells (SMCs). These channels play an important role in regulating the membrane potential and vessel contractility-a role that depends on the vascular bed. Thus, the activity of K+ channels represents one of the main mechanisms regulating the vascular tone in physiological and pathophysiological conditions. Briefly, the activation of K+ channels in SMC leads to hyperpolarization and vasorelaxation, while its inhibition induces depolarization and consequent vascular contraction. Currently, there are four different types of K+ channels described in SMCs: voltage-dependent K+ (KV) channels, calcium-activated K+ (KCa) channels, inward rectifier K+ (Kir) channels, and 2-pore domain K+ (K2P) channels. Due to the fundamental role of K+ channels in excitable cells, these channels are promising therapeutic targets in clinical practice. Therefore, this review discusses the basic properties of the various types of K+ channels, including structure, cellular mechanisms that regulate their activity, and new advances in the development of activators and blockers of these channels. The vascular functions of these channels will be discussed with a focus on vascular SMCs of the human umbilical artery. Then, the clinical importance of K+ channels in the treatment and prevention of cardiovascular diseases during pregnancy, such as gestational hypertension and preeclampsia, will be explored.
-
4.
Potassium channels in the neuronal homeostasis and neurodegenerative pathways underlying Alzheimer's disease: An update.
Villa, C, Suphesiz, H, Combi, R, Akyuz, E
Mechanisms of ageing and development. 2020;:111197
Abstract
With more than 80 subunits, potassium (K+) channels represent a group of ion channels showing high degree of diversity and ubiquity. They play important role in the control of membrane depolarization and cell excitability in several tissues, including the brain. Controlling the intracellular and extracellular K+ flow in cells, they also modulate the hormone and neurotransmitter release, apoptosis and cell proliferation. It is therefore not surprising that an improper functioning of K+ channels in neurons has been associated with pathophysiology of a wide range of neurological disorders, especially Alzheimer's disease (AD). This review aims to give a comprehensive overview of the basic properties and pathophysiological functions of the main classes of K+ channels in the context of disease processes, also discussing the progress, challenges and opportunities to develop drugs targeting these channels as potential pharmacological approach for AD treatment.
-
5.
Potassium channels and their role in glioma: A mini review.
Liu, J, Qu, C, Han, C, Chen, MM, An, LJ, Zou, W
Molecular membrane biology. 2019;(1):76-85
Abstract
K+ channels regulate a multitude of biological processes and play important roles in a variety of diseases by controlling potassium flow across cell membranes. They are widely expressed in the central and peripheral nervous system. As a malignant tumor derived from nerve epithelium, glioma has the characteristics of high incidence, high recurrence rate, high mortality rate, and low cure rate. Since glioma cells show invasive growth, current surgical methods cannot completely remove tumors. Adjuvant chemotherapy is still needed after surgery. Because the blood-brain barrier and other factors lead to a lower effective concentration of chemotherapeutic drugs in the tumor, the recurrence rate of residual lesions is extremely high. Therefore, new therapeutic methods are needed. Numerous studies have shown that different K+ channel subtypes are differentially expressed in glioma cells and are involved in the regulation of the cell cycle of glioma cells to arrest them at different stages of the cell cycle. Increasing evidence suggests that K+ channels express in glioma cells and regulate glioma cell behaviors such as cell cycle, proliferation and apoptosis. This review article aims to summarize the current knowledge on the function of K+ channels in glioma, suggests K+ channels participating in the development of glioma.
-
6.
Beneficial Effects of High Potassium: Contribution of Renal Basolateral K+ Channels.
Staruschenko, A
Hypertension (Dallas, Tex. : 1979). 2018;(6):1015-1022
-
7.
KCTD7-related progressive myoclonus epilepsy.
Van Bogaert, P
Epileptic disorders : international epilepsy journal with videotape. 2016;(S2):115-119
Abstract
Progressive myoclonic epilepsy associated with KCTD7 mutations has been reported in 19 patients from 12 families. Patients show homozygous mutations in the coding regions of the KCTD7 gene. The disease starts in infancy. Patients typically show an initial severe epileptic disorder, with abundant epileptiform discharges on EEG and myoclonic seizures in the foreground, associated with cognitive regression and ataxia. Continuous multifocal myoclonus aggravated by action is observed in more than half of the cases. After a few years, the disease tends to stabilize and long survival can be expected. Some patients remain able to walk independently. The severity of the disease is variable from one patient to another, even within the same family. It is hypothesized that the epileptic disorder may influence the neurological regression observed in patients.
-
8.
KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects.
Lim, CX, Ricos, MG, Dibbens, LM, Heron, SE
Journal of medical genetics. 2016;(4):217-25
Abstract
Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date. Mutations in KCNT1 have also been described in eight unrelated cases of sporadic and familial autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients have a high frequency of associated intellectual disability and psychiatric features. Two mutations in KCNT1 have been associated with both ADNFLE and MMFSI, suggesting that the genotype-phenotype relationship for KCNT1 mutations is not straightforward. Mutations have also been described in several patients with infantile epileptic encephalopathies other than MMFSI. Notably, all mutations in KCNT1 described to date are missense mutations, and electrophysiological studies have shown that they result in increased potassium current. Together, these genetic and electrophysiological studies raise the possibility of delivering precision medicine by treating patients with KCNT1 mutations using drugs that alter the action of potassium channels to specifically target the biological effects of their disease-causing mutation. Such trials are now in progress. Better understanding of the mechanisms underlying KCNT1-related disease will produce further improvements in treatment of the associated severe seizure disorders.
-
9.
Clinical Features of Genetic Cardiac Diseases Related to Potassium Channelopathies.
Adler, A, Viskin, S
Cardiac electrophysiology clinics. 2016;(2):361-72
Abstract
Genetic cardiac diseases related to potassium channelopathies are a group of relatively rare syndromes that includes long QT syndrome, short QT syndrome, Brugada syndrome, and early repolarization syndrome. Patients with these syndromes share a propensity for the development of life-threatening ventricular arrhythmias in the absence of significant cardiac structural abnormalities. Familial atrial fibrillation has also been associated with potassium channel dysfunction but differs from the other syndromes by being a rare cause of a common condition. This article focuses on the clinical features, diagnosis, and management of these syndromes.
-
10.
Genetic Control of Potassium Channels.
Amin, AS, Wilde, AA
Cardiac electrophysiology clinics. 2016;(2):285-306
Abstract
Approximately 80 genes in the human genome code for pore-forming subunits of potassium (K(+)) channels. Rare variants (mutations) in K(+) channel-encoding genes may cause heritable arrhythmia syndromes. Not all rare variants in K(+) channel-encoding genes are necessarily disease-causing mutations. Common variants in K(+) channel-encoding genes are increasingly recognized as modifiers of phenotype in heritable arrhythmia syndromes and in the general population. Although difficult, distinguishing pathogenic variants from benign variants is of utmost importance to avoid false designations of genetic variants as disease-causing mutations.