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Pathophysiology of neurogenic detrusor overactivity
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Alexandra McPencow, Toby C. Chai
The large conductance of calcium-activated potassium channel (BK) has been shown to be important regulator of normal human and mouse DSM contractility.44,45 When BK is open (activated by increased intracellular calcium and/or cellular depolarization), potassium flows out of the cell, thus hyperpolarizing the cell and reducing the ability of the cell to contract and/or generate spontaneous activity. The depiction of BK morphology is shown in Figure 7.5. Each BK channel is composed of 4 units (tetramer) of BK protein. Each BK protein unit has an α-subunit (pore-forming unit) and a β-subunit (regulatory unit). Each α-subunit has seven transmembrane domains, whereas each β-subunit has two transmembrane domains. Alternative splicing of the BK gene (KCNMA1) can further regulate the properties of the BK channel.
Neutrophil extracellular trap-associated molecules: a review on their immunophysiological and inflammatory roles
Published in International Reviews of Immunology, 2022
Abraham U. Morales-Primo, Ingeborg Becker, Jaime Zamora-Chimal
On the other hand, NOX independent-NETosis is instigated by stimuli such as the ionophores A23187 and nigericin, or physiological agents like the granulocyte-macrophage colony-stimulating factor (GM-CSF).21,22 Besides the absence of NOX activity, this process also lacks both NE and MPO proteins for chromatin loosing.21 Instead, this task is performed by PAD4, a peptidyl-arginine deaminase that is activated by binding with calcium ions due to the stimuli-induced calcium influx.23 Once PAD4 gets activated, it translocates inside the nucleus. It will interact with the arginine residues of H3 and H4 histones, converting them into citrulline, neutralizing positive charges in a process called citrullination, consequently decondensing the chromatin.24 Along with this process, kinases such as JNK, PYK2, AKT, p38, and SRC, will trigger their cascades by activating transcription factors, initiating transcription at specific promoters, aiding for chromatin relaxing.25 Interestingly, promoter sites are found citrullinated, showing the synergistic labor of PAD4 and kinases in the formation of NETs.25 Another important step for NOX independent-NETosis exerted by the stimuli-induced calcium influx is the activation of the small-conductance calcium-activated potassium channel 3 (SK3).26 SK3 channels bind Ca+2 to its calmodulin subunit, causing conformational changes and opening the channel.27 Finally, mitochondrial ROS is also necessary for the NET formation and is linked to SK3 activation.26
New methodological approaches to atrial fibrillation drug discovery
Published in Expert Opinion on Drug Discovery, 2021
The small conductance calcium-activated potassium channel (SK channel) has been shown to be predominantly expressed in the atrium and is a potential drug target for AF suppression. [18] SK channel inhibitors UCL1684, N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA), and NS8593 terminated AF in guinea pig hearts in-vivo and ex-vivo without affecting QT interval. [19] The relatively selective SK channel inhibitor NS8593 terminated pacing-induced AF and decreased AF duration and vulnerability without affecting ventricular conduction and repolarization in a horse model. [20] In a porcine model of vernakalant-resistant-sustained AF induced by atrial tachypacing, the SK channel inhibitor AP14145 prolonged atrial refractoriness and reduced AF duration without affecting ventricular refractoriness. [21]
The safety of treating newly diagnosed epilepsy
Published in Expert Opinion on Drug Safety, 2019
Compared to avoiding certain AEDs in genetically at-risk individuals to improve safety, success in using genetic information to improve treatment efficacy has been more limited. In theory, employing specific therapies to causative mutations can potentially minimize the burden of polytherapy and improve epilepsy severity [92]. Mutations in the KCNT1 gene responsible for a type of calcium-activated potassium channel, for example, are associated with the development of severe epilepsies including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In-vitro studies [107] and case series [108] supported the potential use of quinidine, an anti-malarial agent, in KCNT1 epilepsies. However, a recent clinical trial of quinidine in six individuals with ADNFLE caused by KCNT1-mutation resulted in no significant reduction in seizure frequency, possibly because of the limitation of dosage by cardiotoxicity [109].