Pannexin 1 involvement in bladder dysfunction in a multiple sclerosis model

Key pointsr ATP is released through pannexin channels into the lumen of the rat urinary bladder in response to distension or stimulation with bacterial endotoxins.r Luminal ATP plays a physiological role in the control of micturition because intravesical perfusion of apyrase or the ecto-ATPase inhibitor ARL67156 altered reflex bladder activity in the anaesthetized rat.r The release of ATP from the apical and basolateral surfaces of the urothelium appears to be mediated by separate mechanisms because intravesical administration of the pannexin channel antagonist Brilliant Blue FCF increased bladder capacity, whereas I.V. administration did not.r Intravesical instillation of small interfering RNA-containing liposomes decreased pannexin 1 expression in the rat urothelium in vivo and increased bladder capacity.r These data indicate a role for pannexin-mediated luminal ATP release in both the physiological and pathophysiological control of micturition and suggest that urothelial pannexin may be a viable target for the treatment of overactive bladder disorders.Abstract ATP is released from the bladder epithelium, also termed the urothelium, in response to mechanical or chemical stimuli. Although numerous studies have described the contribution of this release to the development of various bladder disorders, little information exists regarding the mechanisms of release. In the present study, we examined the role of pannexin channels in mechanically-induced ATP release from the urothelium. PCR confirmed the presence of pannexin 1 and 2 mRNA in rat urothelial tissue, whereas immunofluorescence experiments localized pannexin 1 to all three layers of the urothelium. During continuous bladder cystometry in anaesthetized rats, inhibition of pannexin 1 channels using carbenoxolone (CBX) or Brilliant Blue FCF (BB-FCF) (1-100 μM, intravesically), or by using intravesical small interfering RNA, increased the interval between voiding contractions. Intravenous administration of BB-FCF (1-100 μg kg −1 ) did not alter bladder activity. CBX or BB-FCF (100 μM intravesically) also decreased basal ATP concentrations in the perfusate from non-distended bladders and inhibited increases in ATP concentrations in response to bladder distension (15 and 30 cmH 2 O pressure). Intravesical perfusion of the ATP diphosphohydrolase apyrase (2 U ml −1 ), or the ATPase inhibitor ARL67156 (10 μM) increased or decreased reflex bladder activity, respectively. Intravesical instillation of bacterial lipopolysaccharides (LPS) (Escherichia coli 055:B5, 100 μg ml −1 ) increased ATP concentrations in the bladder perfusate, and also increased voiding frequency; these effects were suppressed by BB-FCF. These data indicate that pannexin channels contribute to distension-or LPS-evoked ATP release into the lumen of the bladder and that luminal release can modulate voiding function.

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“…Two recent studies have also implicated pannexin channels in the release of ATP from the urothelium (Negoro et al . ; Timoteo et al . ).…”

Section: Discussionmentioning

confidence: 99%

Pannexin 1 channels mediate the release of ATP into the lumen of the rat urinary bladder

Beckel

Daugherty

Tyagi

et al. 2015

The Journal of Physiology

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“…Davis KOMP (allele: Panx1tm1a (KOMP) Wtsi) as heterozygous (HT) mice on C57Bl/6 background and bred to homozygosity (Panx1 KO and Panx1 WT) and maintained in an SPF animal facility at The Albert Einstein College of Medicine. EAE was induced as previously described (15, 20). Clinical signs of disease were scored on a 0–8 scale where, 0: No signs; 1: Loss of tail tone; 2: Paralyzed tail; 3: Hind limb weakness; 4: Hind limb hemi-paralysis; 5: Complete hind limb paralysis; 6: Complete hind limb paralysis with forelimb weakness; 7: Tetraplegia; 8: Moribund.…”

Section: Methodsmentioning

confidence: 99%

Pannexin1 Channels Are Required for Chemokine-Mediated Migration of CD4+ T Lymphocytes: Role in Inflammation and Experimental Autoimmune Encephalomyelitis

Velasquez

Malik²,

Lutz

et al. 2016

The Journal of Immunology

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Pannexin1 (Panx1) channels are large high conductance channels found in all vertebrates that can be activated under several physiological and pathological conditions. Our published data indicates that HIV infection results in the extended opening of Panx1 channels (5 min – 60 min), allowing for the secretion of ATP through the channel pore with subsequent activation of purinergic receptors, which facilitates HIV entry and replication. In the current report we demonstrate that chemokines, which bind CCR5 and CXCR4, especially SDF-1α/CXCL12, result in a transient opening (peak at 5 min) of Panx1 channels found on CD4+ T lymphocytes which induces ATP secretion, focal adhesion kinase phosphorylation, cell polarization and subsequent migration. Increased migration of immune cells is key for the pathogenesis of several inflammatory diseases including multiple sclerosis (MS). Here we show that genetic deletion of Panx1 reduces the number of the CD4+ T lymphocytes migrating into the spinal cord of mice subjected to experimental autoimmune encephalomyelitis, an animal model of MS. Our results indicate that opening of Panx1 channels in response to chemokines is required for CD4+ T lymphocyte migration, and we propose that targeting Panx1 channels could provide new potential therapeutic approaches to decrease the devastating effects of MS and other inflammatory diseases.

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“…A growing number of evidence has implicated microgliosis (Shijie et al, ) and astrogliosis (Moreno et al, ) in the pathogenesis of stress‐induced neurodegeneration. In addition, increased hemichannel activity in glial cells contributes to the activation of these cells, ultimately resulting in neuronal death (Brand‐Schieber et al, ; Orellana et al, ; Negoro et al, ; Takeuchi and Suzumura, ). However, the contribution of oligodendrocytes and myelin under inflammatory conditions remains poorly understood.…”

Section: Resultsmentioning

confidence: 99%

High glucocorticoid levels during gestation activate the inflammasome in hippocampal oligodendrocytes of the offspring

Maturana

Aguirre

Sáez

2016

Developmental Neurobiology

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Exposure to high levels of glucocorticoids (GCs) during early life induces long-lasting neuroinflammation. GCs induce rapid degranulation of mast cells, which release proinflammatory molecules promoting activation of microglia and astrocytes. The possible involvement of oligodendrocytes, however, remains poorly understood. It was studied whether high GC levels during gestation activates the inflammasome in hippocampal oligodendrocytes of mouse offspring. Oligodendrocytes of control pups showed expression of inflammasome components (NLRP3, ACS, and caspase-1) and their levels were increased by prenatal administration of dexamethasone (DEX), a synthetic GC. These cells also showed high levels of IL-1β and TNF-α, revealing activation of the inflammasome. Moreover, they showed increased levels of the P2X receptor and pannexin1, which are associated to inflammasome activation. However, levels of connexins either were not affected (Cx29) or reduced (Cx32 and Cx47). Nonetheless, the functional states of pannexin1 and connexin hemichannels were elevated and directly associated to functional P2X receptors. As observed in DEX-treated brain slices, hemichannel activity first increased in hippocampal mast cells and later in microglia and macroglia. DEX-induced oligodendrocyte hemichannel activity was mimicked by urocortin-II, which is a corticotropin-releasing hormone receptor (CRHR) agonist. Response to DEX and urocortin-II was inhibited by antalarmin (a CRHR blocker) or by mast cells or microglia inhibitors. The increase in hemichannel activity persisted for several weeks after birth and cross-fostering with a control mother did not reverse this condition. It is proposed that activation of the oligodendrocyte inflammasome might be relevant in demyelinating diseases associated with early life exposure to high GC levels. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 625-642, 2017.

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Pannexin 1 involvement in bladder dysfunction in a multiple sclerosis model

Cited by 42 publications

References 56 publications

Pannexin 1 channels mediate the release of ATP into the lumen of the rat urinary bladder

Pannexin 1 channels mediate the release of ATP into the lumen of the rat urinary bladder

Pannexin1 Channels Are Required for Chemokine-Mediated Migration of CD4+ T Lymphocytes: Role in Inflammation and Experimental Autoimmune Encephalomyelitis

High glucocorticoid levels during gestation activate the inflammasome in hippocampal oligodendrocytes of the offspring

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