Circadian coordination of ATP release in the urothelium via connexin43 hemichannels

Sengiku, Atsushi; Ueda, Masakatsu; Kono, Jin; Sano, Tsuyoshi; Nishikawa, Nobuyuki; Kunisue, Sumihiro; Tsujihana, Kojiro; Liou, Louis S.; Kanematsu, Akihiro; Shimba, Shigeki; Doi, Masao; Okamura, Hitoshi; Ogawa, Osamu; Negoro, Hiromitsu

doi:10.1038/s41598-018-20379-0

Cited by 25 publications

(34 citation statements)

References 61 publications

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“…Furthermore, enhanced ATP release is also seen from bladder strips isolated from patients with interstitial cystitis/bladder pain syndrome and neurogenic and idiopathic detrusor overactivity 13–15 . The mechanism underlying ATP release from the urothelium has been shown to integrate both traditional vesicular mechanisms 9,16 , as well as direct release via pannexin and connexin channel proteins 17,18 . A number of studies, however, have shown that urothelial ATP release is controlled by a rise in intracellular calcium concentrations, with agents that interfere with intracellular calcium entry or the liberation of inositol triphosphate (IP 3 ) able to block stretch induced ATP release 9,10,19–23 .…”

Section: Introductionmentioning

confidence: 99%

Purinergic receptor mediated calcium signalling in urothelial cells

Chess‐Williams

Sellers

Brierley

et al. 2019

Sci Rep

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Non-neuronal ATP released from the urothelium in response to bladder stretch is a key modulator of bladder mechanosensation. Whilst non-neuronal ATP acts on the underlying bladder afferent nerves to facilitate sensation, there is also the potential for ATP to act in an autocrine manner, modulating urothelial cell function. The aim of this study was to systematically characterise the functional response of primary mouse urothelial cells (PMUCs) to ATP. PMUCs isolated from male mice (14–16 weeks) were used for live-cell fluorescent calcium imaging and qRT-PCR to determine the expression profile of P2X and P2Y receptors. The majority of PMUCs (74–92%) responded to ATP (1 μM–1 mM), as indicted by an increase in intracellular calcium (iCa2+). PMUCs exhibited dose-dependent responses to ATP (10 nM–1 mM) in both calcium containing (2 mM, EC50 = 3.49 ± 0.77 μM) or calcium free (0 mM, EC50 = 9.5 ± 1.5 μM) buffers. However, maximum iCa2+ responses to ATP were significantly attenuated upon repetitive applications in calcium containing but not in calcium free buffer. qRT-PCR revealed expression of P2X1–6, and P2Y1–2, P2Y4, P2Y6, P2Y11–14, but not P2X7 in PMUCs. These findings suggest the major component of ATP induced increases in iCa2+ are mediated via the liberation of calcium from intracellular stores, implicating functional P2Y receptors that are ubiquitously expressed on PMUCs.

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Section: Introductionmentioning

confidence: 99%

Purinergic receptor mediated calcium signalling in urothelial cells

Chess‐Williams

Sellers

Brierley

et al. 2019

Sci Rep

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“…Previous studies by us and others [8,18] have shown that, in Figure 2. Comparison of the temporal changes in distension-induced luminal ATP release in WT and uCx43KO mice.…”

Section: Evaluation Of Mechanosensitive Urothelial Atp Release In Ucxmentioning

confidence: 60%

“…Additionally, in contrast to prior studies with TRPV1 KO or TRPV4 KO mice [21,23,24] that showed reduced distension-induced urothelial ATP release and inhibition of micturition reflex induced by ATP instillation, recent studies have shown increased urinary frequency in TRPV1 or TRPV4 KO mice compared to WT mice [25]. This discrepancy may come from use of global knockout mice in these reports and differences in experimental approaches, since more physiological approaches that evaluate overall changes in voiding behavior can be influenced by changes in function of these [8]). In uCx43KO mice, downregulation of Cx43 expression in the urothelium results in reduced urothelial ATP release, especially in the animals' active phase (night-time).…”

Section: Discussionmentioning

confidence: 95%

“…These results suggested that suppression of the Cx43 gap junction-mediated coupling in the urothelium and Cx43 hemichannel contribution to urothelial ATP release blunts the coordination of urothelial responses to bladder distension, which attenuates the stimulation of urothelial cells and bladder sensory nerves, particularly during the awake, active phase of the animals, when the levels of Cx43 protein and of its contribution are the most important ( Figure 5). [8]). In uCx43KO mice, downregulation of Cx43 expression in the urothelium results in reduced urothelial ATP release, especially in the animals' active phase (night-time).…”

Section: Discussionmentioning

confidence: 99%

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Urothelium-Specific Deletion of Connexin43 in the Mouse Urinary Bladder Alters Distension-Induced ATP Release and Voiding Behavior

Kono

Ueda

Sengiku

et al. 2021

IJMS

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Connexin43 (Cx43), the main gap junction and hemichannel forming protein in the urinary bladder, participates in the regulation of bladder motor and sensory functions and has been reported as an important modulator of day–night variations in functional bladder capacity. However, because Cx43 is expressed throughout the bladder, the actual role played by the detrusor and the urothelial Cx43 is still unknown. For this purpose, we generated urothelium-specific Cx43 knockout (uCx43KO) mice using Cre-LoxP system. We evaluated the day–night micturition pattern and the urothelial Cx43 hemichannel function of the uCx43KO mice by measuring luminal ATP release after bladder distention. In wild-type (WT) mice, distention-induced ATP release was elevated, and functional bladder capacity was decreased in the animals’ active phase (nighttime) when Cx43 expression was also high compared to levels measured in the sleep phase (daytime). These day–night differences in urothelial ATP release and functional bladder capacity were attenuated in uCx43KO mice that, in the active phase, displayed lower ATP release and higher functional bladder capacity than WT mice. These findings indicate that urothelial Cx43 mediated ATP signaling and coordination of urothelial activity are essential for proper perception and regulation of responses to bladder distension in the animals’ awake, active phase.

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“…1). As for the urinary system, it has been reported that micturition and the storage capacity, as well as Connexin43 expression, show circadian oscillation in the urinary bladder 7,8 . We have reported that robust circadian clock oscillation is observed in the medulla of kidneys, and that the osmotic pressure in the inner medulla shows apparent daily fluctuation 9 .…”

Section: Hierarchical Organization Of the Mammalian Circadian Clockmentioning

confidence: 85%

Circadian clock and cancer: From a viewpoint of cellular differentiation

2020

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Abbreviations & Acronyms AML = acute myeloid leukemia ccg = clock-controlled gene DNMT1 = DNA methyltransferase 1 E19 = embryonic day 19 ES = embryonic stem iPS = induced pluripotent stem MEF = mouse embryonic fibroblast MRT = malignant rhabdoid tumor OSKM = Oct3/4, Sox2, Klf4 and c-Myc Per2 Luc = Per2::Luciferase SCN = suprachiasmatic nucleus SMG = submandibular gland TTFL = transcriptionaltranslational feedback loop UPR = unfolded protein response Correspondence: KazuhiroAbstract: The circadian clock controls and adapts diverse physiological and behavioral processes according to Earth's 24-h cycle of environmental changes. The master pacemaker of the mammalian circadian clock resides in the hypothalamic suprachiasmatic nucleus, but almost all cells throughout the body show circadian oscillations in gene expression patterns and associated functions. Recent studies have shown that the circadian clock gradually develops during embryogenesis. Embryonic stem cells and induced pluripotent stem cells do not show circadian oscillations of gene expression, but gradually develop circadian clock oscillation during differentiation; thus, the developmental program of circadian clock emergence appears closely associated with cellular differentiation. Like embryonic stem cells, certain cancer cell types also lack the circadian clock. Given this similarity between embryonic stem cells and cancer cells, interest is growing in the contributions of circadian clock dysfunction to dedifferentiation and cancer development. In this review, we summarize recent advances in our understanding of circadian clock emergence during ontogenesis, and discuss possible associations with cellular differentiation and carcinogenesis. Considering the multiple physiological functions of circadian rhythms, circadian abnormalities might contribute to a host of diseases, including cancer. Insights on circadian function could lead to the identification of biomarkers for cancer diagnosis and prognosis, as well as novel targets for treatment. Hierarchical organization of the mammalian circadian clockMost organisms have evolved an intrinsic circadian clock to adapt physiological functions to the planet's 24-h environmental cycles. In mammals, the circadian clock controls such physiological and behavioral functions as sleep-wake cycles, metabolism, hormonal secretion, body temperature, immune responses and neuronal functions. 1,2 The master pacemaker of the mammalian circadian clock resides in the SCN of the hypothalamus. A subset of SCN neurons receive a clock-resetting light signal from the retinohypothalamic tract and communicate with other SCN cells to maintain robust circadian oscillations of neuronal activity. These neuronal oscillations in turn synchronize other peripheral oscillators throughout the body through neuronal and hormonal signaling pathways. 3,4 At the cellular and molecular levels, the circadian clock is comprised of a set of core clock genes functionally organized into TTFLs that generate cell-autonomous circadian oscillations in gene ex...

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Circadian coordination of ATP release in the urothelium via connexin43 hemichannels

Cited by 25 publications

References 61 publications

Purinergic receptor mediated calcium signalling in urothelial cells

Purinergic receptor mediated calcium signalling in urothelial cells

Urothelium-Specific Deletion of Connexin43 in the Mouse Urinary Bladder Alters Distension-Induced ATP Release and Voiding Behavior

Circadian clock and cancer: From a viewpoint of cellular differentiation

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