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Ion Channels in Immune Cells
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Devasena Ponnalagu, Shridhar Sanghvi, Shyam S. Bansal, Harpreet Singh
Although chloride channels are important for cell-volume regulation, unfortunately they are often neglected due to their lack of molecular identity and nonselective nature. However, few of the plasma membrane anion channels characterized, such as ClSwell, GABAA, and CFTR, have been implicated in immune cell activation and function12,107–115. The role of chloride channels in the volume regulation of T cells was identified in pioneering research done in the 1980s21. They were defined as VRAC or ClSwell, as the permeability to anions increased in the peripheral blood mononuclear cells (PBMC) upon osmolarity changes. Later, LRRC8A was identified as a molecular component of ClSwell110. It is predicted to be a hexameric channel with a pannexin-like transmembrane topology comprising hetero multimers of LRRC8A and other LRRC8 (-B, -C, -D, and -E) subunits12. Interestingly, a case study demonstrated that a mutation in LRRC8 was responsible for agammaglobulinemia, a congenital syndrome defined by a defect in B cell development116. In patients with agammaglobulinemia, translocation of the LRRC8 gene was observed that led to the truncation of half of the seventh and complete deletion of the eighth and ninth LRR domains located at the C-terminal of the LRRC8 protein, which eventually resulted in the inhibition of B cell development and proliferation116. Furthermore, knockdown of the LRRC8 gene abolished hypotonicity-induced volume regulation in T cells, decreased their proliferation, and induced apoptosis12. Similar to neurons, activation of GABAA receptors in T cells has an inhibitory role. GABA inhibited T cell proliferation and production of IL-2 and IFN-γ in in vitro experiments. A possible mechanism that was proposed is that opening of GABAA receptor channels induces Cl− efflux, cell depolarization, and decreased Ca2+ influx, resulting in inhibition of T cell function12. In patients with cystic fibrosis as well, defects in the CFTR gene were suggested to contribute to the impaired immune response, thus strengthening the role of chloride channels in immune response12.
Physiology of Micturition
Published in Linda Cardozo, Staskin David, Textbook of Female Urology and Urogynecology - Two-Volume Set, 2017
Shachi Tyagi, Pradeep Tyagi, Naoki Yoshimura, Michael B. Chancellor
Afferent Activity. Although the source of Autonomous detrusor Activity is uncleAr, spontAneous contrActile Activity of detrusor myocytes wAs suspected to trigger spontAneous contrActions through gAp junctions [31]. AlternAtively, Another populAtion of cells locAted in vArious sites the blAdder known As interstitiAl cells hAve been proposed for the pAcemAking role in spontAneous Activity of the blAdder [32,33]. InterstitiAl cells hAve been identified in humAn And guineA pig ureter, urethrA, And blAdder body [33–35]. urothelium is believed to secrete pArAcrine fActors thAt seem to reduce the spontAneous Activity of detrusor [30] becAuse the frequency of wholecell CA2 flAshes of detrusor smooth muscle cells wAs higher in prepArAtions with intAct urothelium relAtive to those with denuded urothelium. SuburotheliAl InterstitiAl Cells Distension of blAdder during filling of urine stretches the urothelium And cAuses the nonneuronAl releAse of Acetylcholine (ACh) or Adenosine triphosphAte (AtP) from pAnnexin-1 hemichAnnels [36]. AtP exerts A prominent role on Afferent Arm of micturition reflex As it initiAtes the voiding reflex viA the ActivAtion of P2X 3 receptors on suburotheliAl sensory nerve fibers [35]. The stretch-evoked AtP releAse is increAsed in diseAsed condition such As chronic spinAl cord injury [37,38]. The AtP releAse from stretched urothelium is reported to be further Augmented in Aging And in obstructed blAdder [39–43], which mAy be relAted to increAsed voiding frequency And enhAnced low-threshold Afferent nerve Activity noted in these conditions. elevAted expression of P2X 3 receptor in urothelium And interstitiAl cells hAs been reported in AssociAtion with Aging [40] And in rAt model of blAdder obstruction [44]. AtP is Also A cotrAnsmitter of ACh in the pArAsympAthetic nerves And pArticipAtes in both Afferent And efferent trAnsmissions of micturition reflex [45]. suburotheliAl (or lAminA propriA) interstitiAl cells in the humAn blAdder hAve Also been termed myofibroblAsts As they stAin for vimentin And AlphA-smooth muscle Actin but not for desmin [46]. ImmunohistochemicAl studies show the expression of P2Y receptors, most notAbly P2Y6 receptors [22] And M3 muscArinic receptors in the suburotheliAl interstitiAl cells from guineA pigs [21–25]. These cells Are linked by gAp junctions composed of connexin 43 proteins, which mAke close Appositions with C-fiber nerve endings in the suburothelium to suggest thAt there is A network of functionAlly connected interstitiAl cells immediAtely below the urothelium thAt cAn be modulAted by other nerve fibers [22] (Figure 23.2). IsolAted suburotheliAl interstitiAl cells respond to ApplicAtion of AtP by inducing inwArd currents AssociAted with elevAted intrAcellulAr CA2 [35]. becAuse AtP or ACh is known to be releAsed from the urothelium during blAdder stretch, suburotheliAl interstitiAl cells thAt respond to AtP viA P2Y receptor ActivAtion [21–25] Are in An ideAl position between the urothelium And nerve endings to modify A sensory feedbAck mechAnism [21–25]. In the humAn blAdder, increAsed
Pannexin 1 Channels Contribute to IL-1β Expression via NLRP3/Caspase-1 Inflammasome in Aspergillus Fumigatus Keratitis
Published in Current Eye Research, 2019
Xuejiao Yang, Guiqiu Zhao, Junwei Yan, Rui Xu, Chengye Che, Hengrui Zheng, Guoqiang Zhu, Jie Zhang
Fungi usually enter the corneal stroma through a defect in epithelial cells and then proliferate and finally cause tissue necrosis and inflammation which is an important prerequisite for regeneration.4 The balance between the progression of inflammation and regeneration repair is crucial for the prognoses of fungal keratitis. Innate immunity is the most ancient system to protect multicellular hosts from infection.5 Infiltration of inflammatory cells into the sites of inflamed tissue is largely controlled by the local production of various inflammatory mediators. In the cascade of immune response to injury, ATP externalization was deemed to be the first step leading to maturation and secretion of inflammatory mediators.4 The existing evidence suggests that the release of ATP functions as a “find me signal” to recruit monocytes to the damaged areas.6 Pannexin 1 channels are high permeable channels in the cell membrane to exchange ATP inside and outside of cells.7 During acute systemic inflammation, pannexin 1 channels play important roles in promoting leukocyte adhesion and emigration through the venous wall.8
Oral probenecid improves sperm motility in men with spinal cord injury
Published in The Journal of Spinal Cord Medicine, 2018
Emad Ibrahim, Teodoro C. Aballa, Charles M. Lynne, Nancy L. Brackett
An important pathway leading to activation of the inflammasome is the pannexin-1 channel.11 Activation of the pannexin-1 channel allows intracellular entry of various molecules or proteins which activates the inflammasome, leading to a cascade of events, ultimately resulting in the release of inflammatory cytokines.12 We hypothesized that blocking the pannexin-1 channel would lead to improved sperm motility in men with SCI. We confirmed this hypothesis using probenecid in vitro (unpublished data). Probenecid is an established medication that inhibits the pannexin-1 channel. This drug has been safely used for decades in the treatment of gout.13 The goal of the present study was to determine if probenecid, administered orally to men with SCI, would lead to improved sperm motility.
Mind the gap: connexins and pannexins in platelet function
Published in Platelets, 2021
Kirk a Taylor, Gemma Little, Jonathan M. Gibbins
Connexin and pannexin channels and junctions must be appropriately regulated to prevent leakage of cytosolic content (e.g., ATP) and influx of extracellular ions (e.g., Ca2+), which would disrupt various aspects of cellular homeostasis. To this end, multiple regulatory mechanisms have evolved to control gating of pannexin and connexin channels and ultimately gap junction formation. Such mechanisms include post-translational modifications (PTMs), mechanical stimulation, ischemia, channel gating by extracellular ions and enzymatic cleavage [27,30–35], and are explored herein.