Regulation of ion transport via apical purinergic receptors in intact rabbit airway epithelium

Poulsen, Anja; Klausen, Thomas Levin; Pedersen, Preben Ulrich; Willumsen, Niels J.; Frederiksen, O.

doi:10.1007/s00424-005-1388-4

Cited by 20 publications

(27 citation statements)

References 41 publications

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“…Our conclusion that the P2 receptor mediating regulation of ENaC resides on the apical plasma membrane is also consistent with the prevailing thinking about purinergic regulation of Na ϩ transport and ATP release in collecting duct cells (7,10,14,24,(45)(46)(47)49). Several studies using pharmacological approaches point to the P2Y 2 receptor as possibly being the primary receptor involved in ATP regulation of Na ϩ transport (11,14,24,45,46,48,49).…”

Section: Discussionsupporting

confidence: 90%

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Paracrine Regulation of the Epithelial Na+ Channel in the Mammalian Collecting Duct by Purinergic P2Y2 Receptor Tone

Pochynyuk

Bugaj

Rieg

et al. 2008

Journal of Biological Chemistry

121

166

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Growing evidence implicates a key role for extracellular nucleotides in cellular regulation, including of ion channels and renal function, but the mechanisms for such actions are inadequately defined. We investigated purinergic regulation of the epithelial Na ؉ channel (ENaC) in mammalian collecting duct. We find that ATP decreases ENaC activity in both mouse and rat collecting duct principal cells. ATP and other nucleotides, including UTP, decrease ENaC activity via apical P2Y 2 receptors. ENaC in collecting ducts isolated from mice lacking this receptor have blunted responses to ATP. P2Y 2 couples to ENaC via PLC; direct activation of PLC mimics ATP action. Tonic regulation of ENaC in the collecting duct occurs via locally released ATP; scavenging endogenous ATP and inhibiting P2 receptors, in the absence of other stimuli, rapidly increases ENaC activity. Moreover, ENaC has greater resting activity in collecting ducts from P2Y 2 ؊/؊ mice. Loss of collecting duct P2Y 2 receptors in the knock-out mouse is the primary defect leading to increased ENaC activity based on the ability of direct PLC stimulation to decrease ENaC activity in collecting ducts from P2Y 2 ؊/؊ mice in a manner similar to ATP in collecting ducts from wild-type mice. These findings demonstrate that locally released ATP acts in an autocrine/paracrine manner to tonically regulate ENaC in mammalian collecting duct. Loss of this intrinsic regulation leads to ENaC hyperactivity and contributes to hypertension that occurs in P2Y 2 receptor ؊/؊ mice. P2Y 2 receptor activation by nucleotides thus provides physiologically important regulation of ENaC and electrolyte handling in mammalian kidney. Systemic Naϩ balance influences blood pressure. Consequently, body Na ϩ content is under tight negative-feedback control by the renin-angiotensin-aldosterone system. Discretionary Na ϩ reabsorption in the aldosterone-sensitive distal renal nephron, including the collecting duct, fine-tunes plasma Na ϩ levels. Here, the activity of the luminal epithelial Na ϩ channel (ENaC) 2 is limiting for Na ϩ transport (1-3). ENaC is an end-effector of the renin-angiotensin-aldosterone system with aldosterone increasing ENaC activity. The importance of ENaC and its proper regulation to control of blood pressure is highlighted by several diseases associated with gain and loss of ENaC function (3, 4). For instance, gain of ENaC function results in inappropriate Na ϩ conservation and hypertension (e.g. Liddle syndrome). Conversely, loss of ENaC function results in renal salt wasting associated with hypotension (e.g. pseudohypoaldosteronism type 1).Although extrinsic regulation of ENaC in the distal nephron by hormones originating outside the kidney is considered pivotal to blood pressure control, complementary regulation of ENaC by autocrine/paracrine factors originating from intrarenal sources is just now becoming appreciated. ATP has been identified as a candidate signaling molecule possibly mediating intrinsic control of distal nephron Na ϩ reabsorption (5-14). ATP and other...

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Section: Discussionsupporting

confidence: 90%

“…Moreover, the results are also consistent with related findings regarding ATP-dependent decreases in the amiloride-sensitive Na ϩ current in native collecting ducts (11,14,24), and M-1 (42,45,46) and Madin-Darby canine kidney (7) cells, as well as in mouse and rabbit airway epithelium (42,47) and mouse distal colon (48).…”

Section: Discussionsupporting

confidence: 90%

Paracrine Regulation of the Epithelial Na+ Channel in the Mammalian Collecting Duct by Purinergic P2Y2 Receptor Tone

Pochynyuk

Bugaj

Rieg

et al. 2008

Journal of Biological Chemistry

121

166

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“…The high level of basal PLC activity suggests that paracrine release of ATP tonically inhibits ENaC via P2Y receptors in principal cell monolayers. Similar paracrine regulation of ENaC by endogenous ATP via P2Y receptors was reported for rabbit airway epithelia (26). However, release of intracellular Ca 2ϩ but not PI(4,5)P 2 depletion was identified to be the major cause of this latter inhibition.…”

Section: Discussionsupporting

confidence: 74%

Purinergic control of apical plasma membrane PI(4,5)P₂levels sets ENaC activity in principal cells

Pochynyuk¹,

Bugaj²,

Vandewalle³

et al. 2008

American Journal of Physiology-Renal Physiology

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Pochynyuk O, Bugaj V, Vandewalle A, Stockand JD. Purinergic control of apical plasma membrane PI(4,5)P 2 levels sets ENaC activity in principal cells. Am J Physiol Renal Physiol 294: F38-F46, 2008. First published October 3, 2007 doi:10.1152/ajprenal.00403.2007.-Activity of the epithelial sodium channel (ENaC) is limiting for Na ϩ reabsorption at the distal nephron. Phosphoinositides, such as phosphatidylinositol 4,5-biphosphate [PI(4,5)P 2] modulate the activity of this channel. Activation of purinergic receptors triggers multiple events, including activation of PKC and PLC, with the latter depleting plasma membrane PI(4,5)P 2. Here, we investigate regulation of ENaC in renal principal cells by purinergic receptors via PLC and PI(4,5)P 2. Purinergic signaling rapidly decreases ENaC open probability and apical membrane PI(4,5)P 2 levels with similar time courses. Moreover, inhibiting purinergic signaling with suramin rescues ENaC activity. The PLC inhibitor U73122, but not U73343, its inactive analog, recapitulates the action of suramin. In contrast, modulating PKC signaling failed to affect purinergic regulation of ENaC. Unexpectedly, inhibiting either purinergic receptors or PLC in resting cells dramatically increased ENaC activity above basal levels, indicating tonic activation of purinergic signaling in these polarized renal epithelial cells. Increased ENaC activity was associated with elevation of apical membrane PI(4,5)P 2 levels. Subsequent treatment with ATP in the presence of inhibited purinergic signaling failed to decrease ENaC activity and apical membrane PI(4,5)P 2 levels. Dwell-time analysis reveals that depletion of PI(4,5)P 2 forces ENaC toward a closed state. In contrast, increasing PI(4,5)P 2 levels above basal values locks the channel in an open state interrupted by brief closings. Thus our results suggest that purinergic control of apical membrane PI(4,5)P 2 levels is a major regulator of ENaC activity in renal epithelial cells.phosphoinositides; PLC signaling; P2Y receptors; sodium reabsorption; hypertension THE EPITHELIAL NA ϩ CHANNEL (ENaC) is localized to the apical plasma membrane of many epithelia, including that in the aldosterone-sensitive distal renal nephron. The activity of this channel is limiting for Na ϩ (re)absorption across these epithelia (12,15,31,33,45). ENaC is a critical end-effector of the renin-angiotensin-aldosterone system. Thus ENaC is well positioned to regulate sodium homeostasis and, consequently, blood pressure. The physiological importance of ENaC to negative-feedback regulation of blood pressure is emphasized by inheritable forms of severe hypertension resulting from gain-of-function mutations in the channel (13,21,29,30,32).In contrast, loss-of-function mutations lead to improper salt wasting and low blood pressure (29,30).ENaC is a highly Na ϩ -selective, non-voltage-gated, noninactivating ion channel in the ENaC/Deg superfamily (3,12,15). This channel is heteromeric, comprising three distinct but similar subunits: ␣, ␤, and ␥ (7). Each subunit has NH 2 -and...

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“…Cell deformation by surface tension forces in the proximity of the air-liquid interface causes Ca 2ϩ -dependent exocytotic ATP release (Ramsingh et al, 2011), which may provide a simple sensing mechanisms to detect low content of surface liquid or surfactant, leading via ATP to compensatory secretion of fluid, mucus, and surfactant. Released ATP exerts an autocrine regulation of epithelial NaCl absorption, mainly by inhibiting the amiloride-sensitive epithelial Na ϩ channel (ENaC) and ion conductance via a P2Y receptor-dependent increase in Ca 2ϩ (Poulsen et al, 2005;Bao et al, 2007). Evidence that the released ATP reached sufficient concentrations at the airway surface to activate P2Y 2 receptors has been provided, supporting the view that this is a physiological mechanism for epithelial cell volume regulation (Okada et al, 2006).…”

Section: Lung and Intrapulmonary Airwaysmentioning

confidence: 99%

Purinergic Signaling in the Airways

Burnstock

Brouns²,

Adriaensen³

et al. 2012

Pharmacol Rev

173

158

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Regulation of ion transport via apical purinergic receptors in intact rabbit airway epithelium

Cited by 20 publications

References 41 publications

Paracrine Regulation of the Epithelial Na+ Channel in the Mammalian Collecting Duct by Purinergic P2Y2 Receptor Tone

Paracrine Regulation of the Epithelial Na+ Channel in the Mammalian Collecting Duct by Purinergic P2Y2 Receptor Tone

Purinergic control of apical plasma membrane PI(4,5)P₂levels sets ENaC activity in principal cells

Purinergic Signaling in the Airways

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Regulation of ion transport via apical purinergic receptors in intact rabbit airway epithelium

Cited by 20 publications

References 41 publications

Paracrine Regulation of the Epithelial Na+ Channel in the Mammalian Collecting Duct by Purinergic P2Y2 Receptor Tone

Paracrine Regulation of the Epithelial Na+ Channel in the Mammalian Collecting Duct by Purinergic P2Y2 Receptor Tone

Purinergic control of apical plasma membrane PI(4,5)P2levels sets ENaC activity in principal cells

Purinergic Signaling in the Airways

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Purinergic control of apical plasma membrane PI(4,5)P₂levels sets ENaC activity in principal cells