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Neurons
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
ClC-2 is expressed in cardiac muscle and in neurons. At least in hippocampal CA1 cells, ClC-2 is more localized in apical dendrites. ClC-2 is activated by hyperpolarization, cell swelling, and a rise in [Cl–]i or in extracellular acidity. ClC-2 opens on hyperpolarization but closes only very slowly with depolarization so that it practically does not close during the brief depolarization of an AP. ClC-2 helps to quickly extrude Cl– from neurons in case of high accumulation of Cl– and contributes substantially to the membrane conductance. An increase in Cl– conductance stabilizes the membrane voltage, whereas a reduction in Cl– conductance increases the input resistance and neuronal excitability. It should be noted that hyperpolarization increases the inward current associated with an efflux of Cl– because of their negative charge.
Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
There are relatively few single gene disorders that result in inherited forms of epilepsy, and these are usually caused by mutations in ion channels or neurotransmitter genes. For example, severe myoclonic epilepsy of infancy is caused by mutations in the a1 subunit of the sodium channel gene SCN1A. Mutations in the b1 subunit of the sodium channel gene SCN1B may cause generalized epilepsy with febrile seizures-plus (GEFS +). Benign infantile neonatal epilepsy is caused by mutations in the potassium channel genes, KCNQ2 or KCNQ3. Juvenile myoclonic epilepsy has been associated with mutations in the chloride channel gene CLCN2.
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
NKCC1 channels are required for active extrusion and accumulation of Cl-, respectively. Nonetheless, if ClC-2 is transiently transfected into neurons with high intra-cellular Cl-, such as dorsal root ganglion neurons, GABA is no longer depolarizing in these neurons but rather becomes hyperpolarizing due to shunting inhibition and changes in membrane resistance.27 By analogy, ClC-2 expression would be predicted to be low in the early postnatal brain but increase progressively beginning around PN 6 to 10, and this is indeed the case in the neocortex.28 Taken together, these studies demonstrate the critical role played by these three Cl- transporters in determining whether a particular cell’s response to GABA is excitatory or inhibitory.
Pharmacotherapeutic advances for chronic idiopathic constipation in adults
Published in Expert Opinion on Pharmacotherapy, 2022
Gabrio Bassotti, Paolo Usai Satta, Ginevra Berti, Mariantonia Lai, Vincenzo Villanacci, Massimo Bellini
Lubiprostone was approved by the Food and Drug Administration in 2006 to treat CIC in adults. It is a secretagogue drug, prostone analog, bicyclic fatty acid metabolite of prostaglandin E1. Lubiprostone is a selective locally activator of type two chloride channel (ClC2), that is highly selective for chloride. The ClC-2 channels are widely present in the human gastrointestinal (GI) tract (stomach, small intestine, colon) and have several important functions, such as maintenance of membrane cell potential, pH and cell volume regulation, and participation in Cl transport and fluid secretion. Lubiprostone acts on the apical surface of the intestinal epithelium activating the ClC-2 channel to allow luminal secretion of chloride that promotes water release. This increased secretion improves intestinal and colonic motility and softens the stool, making their passage easier [32]. Clinical studies (Table 2) confirmed the efficacy of lubiprostone: treated patients reported an increase of spontaneous bowel movements (SBMs) and an improvement of stool consistency and of abdominal bloating [33–36]. Some studies also showed an improvement of quality of life compared with baseline, but only in long-term therapy [37]. The more frequent side effects consist of diarrhea, nausea and headache [38,39]. The most important concern about lubiprostone is the high cost [40]: a one-month supply of lubiprostone costs approximately $178. To date, the drug is commercialized in US and India.
Evaluation of efficacy and safety of lubiprostone in patients with chronic constipation
Published in Scandinavian Journal of Gastroenterology, 2021
Yukiko Handa, Shinya Fukushima, Shogen Yo, Motoyasu Osawa, Takahisa Murao, Osamu Handa, Hiroshi Matsumoto, Eiji Umegaki, Akiko Shiotani
In another randomized, double-blind, placebo-controlled, pharmacodynamic study using barostat-manometry endoscopically placed in 60 healthy volunteers, there were significant gender differences in colonic compliance and postprandial colonic tone [26]. Lubiprostone decreased colonic compliance and postprandial colonic tone in women (likely responsible for relief of constipation), and did increase the pain sensation thresholds in women. There may be the effect of sex hormones on type 2 chloride (ClC-2) channels, although the mechanism for the gender differences remains unclear [27]. Another potential pathway leading to nausea is through activation of chemoreceptors from absorbed metabolites. Lubiprostone exerts a local effect at the enterocyte surface where it is almost completely metabolized. Nevertheless, its active metabolite appears in low concentrations in the serum, possibly activating central nausea pathways [28]. However, the precise mechanism of nausea remains unclear, and it is difficult to predict the development of such troublesome symptoms before administration.
Efficacy and safety of plecanatide in treating constipation predominant irritable bowel syndrome
Published in Expert Opinion on Pharmacotherapy, 2018
FDA approved medications for IBS-C include lubiprostone (activates ClC-2 Chloride channels), linaclotide (guanyl cyclase C agonist) and tegaserod (5-hydroxytrypamine type-4 agonist). Plecanatide is approved for chronic idiopathic constipation with the Supplemental New Drug Application for IBS-C submitted.