Erratum: Corrigendum: Pannexin1 channels dominate ATP release in the cochlea ensuring endocochlear potential and auditory receptor potential generation and hearing

Abstract Pannexin1 (Panx1) is a gap junction gene in vertebrates whose proteins mainly function as non-junctional channels on the cell surface. Panx1 channels can release ATP under physiological conditions and play critical roles in many physiological and pathological processes. Here, we report that Panx1 deficiency can reduce ATP release and endocochlear potential (EP) generation in the cochlea inducing hearing loss. Panx1 extensively expresses in the cochlea, including the cochlear lateral wall. We found that deletion of Panx1 in the cochlear lateral wall almost abolished ATP release under physiological conditions. Positive EP is a driving force for current through hair cells to produce auditory receptor potential. EP generation requires ATP. In the Panx1 deficient mice, EP and auditory receptor potential as measured by cochlear microphonics (CM) were significantly reduced. However, no apparent hair cell loss was detected. Moreover, defect of connexin hemichannels by deletion of connexin26 (Cx26) and Cx30, which are predominant connexin isoforms in the cochlea, did not reduce ATP release under physiological conditions. These data demonstrate that Panx1 channels dominate ATP release in the cochlea ensuring EP and auditory receptor potential generation and hearing. Panx1 deficiency can reduce ATP release and EP generation causing hearing loss.

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Endocochlear potential generation is associated with intercellular communication in the stria vascularis: Structural analysis in the viable dominant spotting mouse mutant

Cell and Tissue Research ◽

10.1007/bf00309888 ◽

1990 ◽

Vol 262 (2) ◽

pp. 329-337 ◽

Cited By ~ 31

Author(s):

Lynn Carlisle ◽

Karen Steel ◽

Andrew Forge

Keyword(s):

Structural Analysis ◽

Intercellular Communication ◽

Stria Vascularis ◽

Endocochlear Potential ◽

Mouse Mutant ◽

Potential Generation ◽

Dominant Spotting

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Involvement of VNUT-exocytosis in transient receptor potential vanilloid 4-dependent ATP release from gastrointestinal epithelium

PLoS ONE ◽

10.1371/journal.pone.0206276 ◽

2018 ◽

Vol 13 (10) ◽

pp. e0206276 ◽

Cited By ~ 7

Author(s):

Hiroshi Mihara ◽

Kunitoshi Uchida ◽

Schuichi Koizumi ◽

Yoshinori Moriyama

Keyword(s):

Transient Receptor Potential ◽

Atp Release ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Gastrointestinal Epithelium ◽

Transient Receptor

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Activation of transient receptor potential (TRP) channels by hypoosmolar solution: an endogenous mechanism of ATP release and afferent nerve activation

10.1183/1393003.congress-2017.oa4410 ◽

2017 ◽

Author(s):

Sara Bonvini ◽

Eric Dubuis ◽

John Adcock ◽

Michael Wortley ◽

Mark Birrell ◽

...

Keyword(s):

Transient Receptor Potential ◽

Trp Channels ◽

Atp Release ◽

Receptor Potential ◽

Afferent Nerve ◽

Transient Receptor

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Mechanosensor transient receptor potential vanilloid member 4 (TRPV4) regulates mouse cholangiocyte secretion and bile formation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00176.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. G277-G287

Author(s):

Qin Li ◽

Charles Kresge ◽

Kristy Boggs ◽

Julie Scott ◽

Andrew Feranchak

Keyword(s):

Fluid Flow ◽

Bile Flow ◽

Transient Receptor Potential ◽

Atp Release ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Bile Formation ◽

Transport Pathways ◽

Transient Receptor

Mechanosensitive signaling has emerged as a mechanism for the regulation of cholangiocyte transport and bile formation. The mechanical effect of fluid-flow, or shear, at the apical membrane of cholangiocytes regulates secretion through a process involving increases in [Ca2+]i and activation of Ca2+-activated Cl− channels. However, the initiating steps translating shear force to increases in intracellular calcium concentration ([Ca2+]i) are unknown. Transient receptor potential vanilloid member 4 (TRPV4), a nonselective cation channel present in the apical membrane of cholangiocytes, has been proposed as a potential mechanosensor. The aim of the present studies was to determine the potential role of TRPV4 in initiating mechanosensitive signaling in response to fluid-flow in cholangiocytes. TRPV4 expression was confirmed in both small and large mouse cholangiocytes. Exposure of cells to either fluid flow or specific TRPV4 pharmacological agonists rapidly increased both [Ca2+]i and membrane cation currents. Both flow- and agonist-stimulated currents displayed identical biophysical properties and were inhibited in the presence of TRPV4 antagonists or in cells after transfection with TRPV4 small interfering RNA. Transfection of mouse cholangiocytes with a TRPV4-enhanced green fluorescent protein construct increased the expression of TRPV4 and the magnitude of flow-stimulated currents. A specific TRPV4 agonist significantly increased the biliary concentration of ATP and bile flow in live mice when administered intravenously and increased ATP release from cholangiocyte monolayers when applied exogenously. The findings are consistent with a model in which activation of cholangiocyte TRPV4 translates shear force into an acute rise in membrane cation permeability, [Ca2+]i, ATP release, and bile flow. Understanding the role of mechanosensitive transport pathways may provide novel insights to modulate bile flow for the treatment of cholestatic liver disorders. NEW & NOTEWORTHY These studies functionally characterize TRPV4 as a mechanosensitive channel in mouse cholangiocytes. By mediating a rapid rise in intracellular Ca2+, necessary for Ca2+-dependent secretion, TRPV4 represents a mechanosensor responsible for translating fluid flow into intracellular signaling and biliary secretion. Furthermore, intravenous infusion of a specific TRPV4 agonist increases bile flow in live mice. Understanding the role of TRPV4 in mechanosensitive transport pathways may provide novel insights to modulate bile flow during cholestasis.

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The Ionic Mechanisms of Receptor Potential Generation

Mechanoreceptors ◽

10.1007/978-3-642-72935-5_4 ◽

1988 ◽

pp. 64-95

Author(s):

George N. Akoev ◽

Boris V. Krylov ◽

Nikolai P. Alekseev

Keyword(s):

Receptor Potential ◽

Potential Generation ◽

Ionic Mechanisms

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TRPV4 blockade reduces voiding frequency, ATP release, and pelvic sensitivity in mice with chronic urothelial overexpression of NGF

AJP Renal Physiology ◽

10.1152/ajprenal.00147.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. F1695-F1706 ◽

Cited By ~ 1

Author(s):

Beatrice M. Girard ◽

Susan E. Campbell ◽

Megan Perkins ◽

Harrison Hsiang ◽

Katharine Tooke ◽

...

Keyword(s):

Urinary Bladder ◽

Transient Receptor Potential ◽

Atp Release ◽

Brefeldin A ◽

Receptor Potential ◽

Fold Increase ◽

Void Volume ◽

Bladder Function ◽

Transient Receptor Potential Vanilloid ◽

Transient Receptor

Transient receptor potential vanilloid family member 4 (TRPV4) transcript and protein expression increased in the urinary bladder and lumbosacral dorsal root ganglia of transgenic mice with chronic urothelial overexpression of nerve growth factor (NGF-OE). We evaluated the functional role of TRPV4 in bladder function with open-outlet cystometry, void spot assays, and natural voiding (Urovoid) assays with the TRPV4 antagonist HC-067047 (1 μM) or vehicle in NGF-OE and littermate wild-type (WT) mice. Blockade of TRPV4 at the level of the urinary bladder significantly ( P ≤ 0.01) increased the intercontraction interval (2.2-fold) and void volume (2.6-fold) and decreased nonvoiding contractions (3.0-fold) in NGF-OE mice, with lesser effects (1.3-fold increase in the intercontraction interval and 1.3-fold increase in the void volume) in WT mice. Similar effects of TRPV4 blockade on bladder function in NGF-OE mice were demonstrated with natural voiding assays. Intravesical administration of HC-067047 (1 µM) significantly ( P ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in littermate WT mice. Blockade of urinary bladder TRPV4 or intravesical infusion of brefeldin A significantly ( P ≤ 0.01) reduced (2-fold) luminal ATP release from the urinary bladder in NGF-OE and littermate WT mice. The results of the present study suggest that TRPV4 contributes to luminal ATP release from the urinary bladder and increased voiding frequency and pelvic sensitivity in NGF-OE mice.

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PAR-2 activation enhances weak acid-induced ATP release through TRPV1 and ASIC sensitization in human esophageal epithelial cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00162.2015 ◽

2015 ◽

Vol 309 (8) ◽

pp. G695-G702 ◽

Cited By ~ 14

Author(s):

Liping Wu ◽

Tadayuki Oshima ◽

Jing Shan ◽

Hiroo Sei ◽

Toshihiko Tomita ◽

...

Keyword(s):

Epithelial Cells ◽

Transient Receptor Potential ◽

Atp Release ◽

Receptor Potential ◽

Weak Acid ◽

Transient Receptor Potential Vanilloid ◽

Esophageal Epithelial Cells ◽

Transient Receptor ◽

Esophageal Hypersensitivity ◽

Interfering Rna

Esophageal visceral hypersensitivity has been proposed to be the pathogenesis of heartburn sensation in nonerosive reflux disease. Protease-activated receptor-2 (PAR-2) is expressed in human esophageal epithelial cells and is believed to play a role in inflammation and sensation. PAR-2 activation may modulate these responses through adenosine triphosphate (ATP) release, which is involved in transduction of sensation and pain. The transient receptor potential vanilloid receptor 1 (TRPV1) and acid-sensing ion channels (ASICs) are both acid-sensitive nociceptors. However, the interaction among these molecules and the mechanisms of heartburn sensation are still not clear. We therefore examined whether ATP release in human esophageal epithelial cells in response to acid is modulated by TRPV1 and ASICs and whether PAR-2 activation influences the sensitivity of TRPV1 and ASICs. Weak acid (pH 5) stimulated the release of ATP from primary human esophageal epithelial cells (HEECs). This effect was significantly reduced after pretreatment with 5-iodoresiniferatoxin (IRTX), a TRPV1-specific antagonist, or with amiloride, a nonselective ASIC blocker. TRPV1 and ASIC3 small interfering RNA (siRNA) transfection also decreased weak acid-induced ATP release. Pretreatment of HEECs with trypsin, tryptase, or a PAR-2 agonist enhanced weak acid-induced ATP release. Trypsin treatment led to the phosphorylation of TRPV1. Acid-induced ATP release enhancement by trypsin was partially blocked by IRTX, amiloride, or a PAR-2 antagonist. Conversely, acid-induced ATP release was augmented by PAR-2 activation through TRPV1 and ASICs. These findings suggested that the pathophysiology of heartburn sensation or esophageal hypersensitivity may be associated with the activation of PAR-2, TRPV1, and ASICs.

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