Potassium Channel Mutations in Epilepsy

2020 ◽  
Author(s):  
Elizabeth E. Palmer
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
Rare Variants ◽  
Cortical Excitability ◽  
Genetic Diagnosis ◽  
Neurodevelopmental Outcome ◽  
Phenotypic Characteristics ◽  
Α Subunit ◽  
The Impact ◽  
Α Subunits

This chapter describes recent advances in understanding the clinical significance of rare variants in potassium channel genes in the causation of epilepsy. The α subunits of potassium channels fall into three major families, which are encoded by at least 70 different genes, of which at least 40 are brain-expressed. Brain-expressed potassium channels, in both nerve and glial cells, have complex roles in the regulation of neurodevelopment and cortical excitability. The chapter discusses the 20 potassium channel α-subunit genes in which rare variants have been linked to a wide variety of neurocognitive phenotypes. Advances in the understanding of how gene variants affect channel function to result in neuronal dysfunction and epilepsy are discussed, as well as descriptions of the phenotypic characteristics of the disorder and how a genetic diagnosis currently impacts clinical management. The rapid discovery of potassium channelopathies causal of epilepsy needs to be matched by improved understanding of the impact of individual variants within the human brain in order to develop truly targeted therapies that will result in seizure control and potentially improved neurodevelopmental outcome.

A form of Autoimmune Diabetes in Adults Named LADA – An Update on Essential Features and Controversies

2019 ◽  
Vol 15 (3) ◽  
pp. 172-173 ◽  
Author(s):  
Valdemar Grill ◽  
Bjørn O. Åsvold
Keyword(s):  
Genetic Background ◽  
Clinical Utility ◽  
Autoimmune Diabetes ◽  
Classical Type ◽  
Phenotypic Characteristics ◽  
Latent Autoimmune Diabetes ◽  
The Impact

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than “classical” type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis has been challenged. Despite the absence of a genetic background that is exclusive to LADA, this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems as to therapy and follow-up perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.

scholarly journals Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals Transcranial Magnetic Stimulation as a Tool to Investigate Motor Cortex Excitability in Sport

2021 ◽  
Vol 11 (4) ◽  
pp. 432
Author(s):  
Fiorenzo Moscatelli ◽  
Antonietta Messina ◽  
Anna Valenzano ◽  
Vincenzo Monda ◽  
Monica Salerno ◽  
...  
Keyword(s):  
Transcranial Magnetic Stimulation ◽  
Motor Cortex ◽  
Magnetic Stimulation ◽  
Motor Coordination ◽  
Cortical Excitability ◽  
Non Invasive ◽  
Motor Cortex Excitability ◽  
Invasive Method ◽  
And Control ◽  
The Impact

Transcranial magnetic stimulation, since its introduction in 1985, has brought important innovations to the study of cortical excitability as it is a non-invasive method and, therefore, can be used both in healthy and sick subjects. Since the introduction of this cortical stimulation technique, it has been possible to deepen the neurophysiological aspects of motor activation and control. In this narrative review, we want to provide a brief overview regarding TMS as a tool to investigate changes in cortex excitability in athletes and highlight how this tool can be used to investigate the acute and chronic responses of the motor cortex in sport science. The parameters that could be used for the evaluation of cortical excitability and the relative relationship with motor coordination and muscle fatigue, will be also analyzed. Repetitive physical training is generally considered as a principal strategy for acquiring a motor skill, and this process can elicit cortical motor representational changes referred to as use-dependent plasticity. In training settings, physical practice combined with the observation of target movements can enhance cortical excitability and facilitate the process of learning. The data to date suggest that TMS is a valid technique to investigate the changes in motor cortex excitability in trained and untrained subjects. Recently, interest in the possible ergogenic effect of non-invasive brain stimulation in sport is growing and therefore in the future it could be useful to conduct new experiments to evaluate the impact on learning and motor performance of these techniques.

scholarly journals Remodeling of Arterial Tone Regulation in Postnatal Development: Focus on Smooth Muscle Cell Potassium Channels

2021 ◽  
Vol 22 (11) ◽  
pp. 5413
Author(s):  
Anastasia A. Shvetsova ◽  
Dina K. Gaynullina ◽  
Olga S. Tarasova ◽  
Rudolf Schubert
Keyword(s):  
Smooth Muscle ◽  
Potassium Channels ◽  
Potassium Channel ◽  
Postnatal Development ◽  
Sympathetic Innervation ◽  
Treatment Strategies ◽  
Muscle Membrane ◽  
Postnatal Life ◽  
Vascular Control ◽  
Bkca Channels

Maturation of the cardiovascular system is associated with crucial structural and functional remodeling. Thickening of the arterial wall, maturation of the sympathetic innervation, and switching of the mechanisms of arterial contraction from calcium-independent to calcium-dependent occur during postnatal development. All these processes promote an almost doubling of blood pressure from the moment of birth to reaching adulthood. This review focuses on the developmental alterations of potassium channels functioning as key smooth muscle membrane potential determinants and, consequently, vascular tone regulators. We present evidence that the pattern of potassium channel contribution to vascular control changes from Kir2, Kv1, Kv7 and TASK-1 channels to BKCa channels with maturation. The differences in the contribution of potassium channels to vasomotor tone at different stages of postnatal life should be considered in treatment strategies of cardiovascular diseases associated with potassium channel malfunction.

KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways

2021 ◽  
pp. 1-15
Author(s):  
Ping Xu ◽  
Xiao Mo ◽  
Ruixue Xia ◽  
Long Jiang ◽  
Chengfei Zhang ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Lung Adenocarcinoma ◽  
Potassium Channel ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Biology ◽  
Erk Signaling ◽  
Mesenchymal Transition

BACKGROUND: Potassium channels, encoded by more than seventy genes, are cell excitability transmembrane proteins and become evident to play essential roles in tumor biology. OBJECTIVE: The deregulation of potassium channel genes has been related to cancer development and patient prognosis. The objective of this study is to understand the role of potassium channels in lung cancer. METHODS: We examined all potassium channel genes and identified that KCNN4 is the most significantly overexpressed one in lung adenocarcinoma. The role and mechanism of KCNN4 in lung adenocarcinoma were further investigated by in vitro cell and molecular assay and in vivo mouse xenograft models. RESULTS: We revealed that the silencing of KCNN4 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma. Further studies showed that knockdown of KCNN4 promotes cell apoptosis, induces cell cycle arrested in the S phase, and is associated with the epithelial to mesenchymal transition (EMT) process. Most importantly, we demonstrated that KCNN4 regulates the progression of lung adenocarcinoma through P13K/AKT and MEK/ERK signaling pathways. The use of inhibitors that targeted AKT and ERK also significantly inhibit the proliferation and metastasis of lung adenocarcinoma cells. CONCLUSIONS: This study investigated the function and mechanism of KCNN4 in lung adenocarcinoma. On this basis, this means that KCNN4 can be used as a tumor marker for lung adenocarcinoma and is expected to become an important target for a potential drug.

scholarly journals WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 484
Author(s):  
Dongchen An ◽  
Steve Peigneur ◽  
Jan Tytgat
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
G Protein ◽  
Cannabinoid Receptors ◽  
Inward Rectifier ◽  
Xenopus Laevis Oocyte ◽  
Inward Rectifier Potassium Channels ◽  
Wide Range ◽  
Cb2 Receptors ◽  
G Protein Coupled

The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. The present study established and validated the functional expression in a Xenopus laevis oocyte expression system of CB1 and CB2 receptors, interacting with heteromeric GIRK1/2 channels and a regulator of G protein signaling, RGS4. This ex vivo system enables the discovery of a wide range of ligands interacting orthosterically or allosterically with CB1 and/or CB2 receptors. WIN55,212-2, a non-selective agonist of CB1 and CB2, was used to explore the CB1- or CB2-GIRK1/2-RGS4 signaling cascade. We show that WIN55,212-2 activates CB1 and CB2 at low concentrations whereas at higher concentrations it exerts a direct block of GIRK1/2. This illustrates a dual modulatory function, a feature not described before, which helps to explain the adverse effects induced by WIN55,212-2 in vivo. When comparing the effects with other typical cannabinoids such as Δ9-THC, CBD, CP55,940, and rimonabant, only WIN55,212-2 can significantly block GIRK1/2. Interestingly, the inward rectifier potassium channel, IRK1, a non-G protein-coupled potassium channel important for setting the resting membrane voltage and highly similar to GIRK1 and GIRK2, is not sensitive to WIN55,212-2, Δ9-THC, CBD, CP55,940, or rimonabant. From this, it is concluded that WIN55,212-2 selectively blocks GIRK1/2.

Identification of domains that control the heteromeric assembly of Kir5.1/Kir4.0 potassium channels

2003 ◽  
Vol 284 (4) ◽  
pp. C910-C917 ◽  
Author(s):  
Angelos-Aristeidis Konstas ◽  
Christoph Korbmacher ◽  
Stephen J. Tucker
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
Functional Diversity ◽  
Kir Channels ◽  
Selective Interaction ◽  
Inwardly Rectifying ◽  
In Cells ◽  
Heteromeric Channels

Heteromultimerization between different inwardly rectifying (Kir) potassium channel subunits is an important mechanism for the generation of functional diversity. However, little is known about the mechanisms that control this process and that prevent promiscuous interactions in cells that express many different Kir subunits. In this study, we have examined the heteromeric assembly of Kir5.1 with other Kir subunits and have shown that this subunit exhibits a highly selective interaction with members of the Kir4.0 subfamily and does not physically associate with other Kir subunits such as Kir1.1, Kir2.1, and Kir6.2. Furthermore, we have identified regions within the Kir4.1 subunit that appear to govern the specificity of this interaction. These results help us to understand the mechanisms that control Kir subunit recognition and assembly and how cells can express many different Kir channels while maintaining distinct subpopulations of homo- and heteromeric channels within the cell.

scholarly journals Activation-inactivation of potassium channels and development of the potassium-channel spike in internally perfused squid giant axons.

1981 ◽  
Vol 78 (1) ◽  
pp. 43-61 ◽  
Author(s):  
I Inoue
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
Voltage Clamp ◽  
Time Constant ◽  
Equilibrium Potential ◽  
Giant Axons ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Time Courses ◽  
Calcium Permeability

A spike that is the result of calcium permeability through potassium channels was separated from the action potential is squid giant axons internally perfused with a 30 mM NaF solution and bathed in a 100 mM CaCl2 solution by blocking sodium channels with tetrodotoxin. Currents through potassium channels were studied under voltage clamp. The records showed a clear voltage-dependent inactivation of the currents. The inactivation was composed of at least two components; one relatively fast, having a time constant of 20--30 ms, and the other very slow, having a time constant of 5--10 s. Voltage clamp was carried out with a variety of salt compositions in both the internal and external solutions. A similar voltage-dependent inactivation, also composed of the two components, was recognized in all the current through potassium channels. Although the direction and intensity of current strongly depended on the salt composition of the solutions, the time-courses of these currents at corresponding voltages were very similar. These results strongly suggest that the inactivation of the currents in attributable to an essential, dynamic property of potassium channels themselves. Thus, the generation of a potassium-channel spike can be understood as an event that occurs when the equilibrium potential across the potassium channel becomes positive.

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