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Investigation of Sudden Cardiac Death
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Potassium channels play a role in the repolarization of the cardiac action potential, and anomalies in the rate of cardiac repolarization can lead to SCD. Notably, KCNH2 which encodes the Kv11.1 channel that regulates the rapid component of the delayed rectifier potassium current; and KCNQ1 which encodes the Kv7.1 channel that regulates the slow delayed rectifier current are important targets. Several KCNH2 and KCNQ1 mutations are present in LQTS. Many of the hundreds of mutations are unique to a family or very rare. Approximately 5% of families have two mutations, and these tend to be more severely affected. Two mutations on opposite chromosomes in either the LQT1 or LQT5 gene causes a severe autosomal recessive form of LQTS usually with associated sensorineural deafness, low gastric-acid secretion and iron deficiency anaemia (Jervell and Lange-Nielsen syndrome). However, 25% of families with LQTS do not yet have a recognized mutation.
Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
No effective therapies exist currently for these disorders. Recent advances in gene-specific treatment have been made possible through development of antisense oligonucleotide (ASO) technology for gene suppression. ASO treatment has already advanced to clinical trials for the polyglutamine disorder, Huntington's disease.17 ASO-based therapies hold great promise in the polyglutamine SCAs as suggested by improvement of motor dysfunction in mouse models of disease.18–20 A shared mechanism of neuronal dysfunction due to potassium channel dysregulation has also been identified, and studies aimed to restore ion channel activity are underway.12 Current treatment remains supportive. Symptomatic medications that have been reported to be of some utility are: Cholinergic agents: physostigmine, lecithin, and choline chloride.GABAergic drugs: baclofen and sodium valproate.Serotonergic compounds: L-5–hydroxytryptophan combined with a peripheral decarboxylase inhibitor, and buspirone hydrochloride.
The Opioid Epidemic
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Opioid receptors are G protein-coupled receptors (GPCR) with seven transmembrane helical loops—three intracellular loops and three extracellular loops. The extracellular loops contain the pocket in which the signaling molecules bind. Acute stimulation of the receptor results in activation of the G-protein and a blocking of the voltage-gated dependent calcium channel which prevents the flow of calcium into the neurons. A potassium channel is also activated—pumping K+ ions out of the neuron. The result is hyperpolarization, activation of components of the mitogen-activated proteins (MAP) kinase cascade, and a decrease in neurotransmitter release such as glutamate and substance P.1 Ultimately analgesia results.
Is kratom (Mitragyna speciosa Korth.) use associated with ECG abnormalities? Electrocardiogram comparisons between regular kratom users and controls
Published in Clinical Toxicology, 2021
Mohammad Farris Iman Leong Abdullah, Kok Leng Tan, Suresh Narayanan, Novline Yuvashnee, Nelson Jeng Yeou Chear, Darshan Singh, Oliver Grundmann, Jack E. Henningfield
Two in vitro studies have suggested that mitragynine may be associated with an increased risk for cardiotoxicity, but their relevance to human kratom users has not been confirmed. These laboratory findings showed that mitragynine can inhibit the human ether-a-go-go-related gene (hERG) which encodes for potassium channels involved in conducting the rapid inward and outward components of delayed rectifier potassium current (IKr). These potassium channels are essential for the repolarisation of action potentials in myocardial cells. This, in turn, prolongs the cardiac action potential and leads to a prolonged QT interval. Consequently, a prolonged QT interval will increase the risk of torsades de pointes. The inhibition of hERG encoded potassium channels is due to the interaction of mitragynine with a high-affinity drug binding site in the cavity of the hERG channel pore rather than to inhibition of the hERG mRNA. Mitragynine also inhibits the G protein-coupled inward rectifier potassium (GIRK) channel in a dose-dependent manner, and this leads to inhibition of the inward-rectifying potassium current (IKACh), which may produce added cardiotoxicity risks [13,14]. These studies suggest the possibility of cardiotoxicity in humans, but the generalisability to human kratom consumption warrants further study. The goal of our study was to investigate the prevalence of electrocardiogram (ECG) abnormalities in general and QTc intervals in particular in regular kratom users compared with non-kratom-using controls.
Potassium channels as prominent targets and tools for the treatment of epilepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Most potassium channels are gated by transmembrane voltage, intracellular Ca2+, and several physiological mediators such as G-proteins. The role of K+ in membrane physiology has been extensively studied in rodent models as basic electrophysiological properties and bursting patterns of primate central neurons are generally similar to those reported for the rodent [30]. Most attention is usually paid to pyramidal neurons, as they are the most numerous in the cortex (~80% of all neurons). The experimentally identified reversal potential of K+ in neocortical neurons (rodent brain slice, layer 5) is ~ −93 mV, while their resting potentials are about – 80 mV [11]. According to the Hodgkin–Huxley theory, the opening of K+ channels during the action potential produces a negative shift of the transmembrane potential to repolarize the neuron (Figure 2b-c). Thus, K+ currents reduce neuronal excitability immediately after each action potential.
New methodological approaches to atrial fibrillation drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Potassium channel blockers are classified as class 3 AAD in the Vaughan-William’s classification. Blocking of potassium channels with outward current aims to prolong action potential duration and the effective refractory period, thereby disrupting the reentry mechanisms that underlie AF. AADs with predominantly potassium channel-blocking properties such as ibutilide and dofetilide are used in pharmacological cardioversion of AF; sotalol and dofetilide are used for long-term rhythm control of AF in countries where they are available. Other multi-channel blockers such as amiodarone and dronedarone also have potassium channel blocking properties. Prolongation of QTc interval is common with these agents and carries the risk of Torsades de pointes. There is interest in developing atrial specific potassium channel blockers that will not prolong the QTc interval. Achieving atrial-specificity in potassium channel blockade can theoretically be achieved by focusing on subsets of potassium channels that are predominantly expressed in atrial cardiomyocytes but not in the ventricles. Several agents against potassium channels expressed predominantly in the atrium have been explored and have been summarized in previous reviews. [11,12]