Cellular ATP release by the cystic fibrosis transmembrane conductance regulator

Prat, Adriana G.; Reisin, Ignacio L.; Ausiello, Dennis A.; Cantiello, Horacio F.

doi:10.1152/ajpcell.1996.270.2.c538

Cited by 78 publications

(71 citation statements)

References 20 publications

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“…2). There are currently several postulated mechanisms for ATP release, including cytolysis, ATP-binding cassette (ABC) proteins (15)(16)(17)(18)(19)(20), and/or neighboring ion channels (53), or through vesicles during exocytosis (22)(23)(24). However, although the mechanism for ATP release by platelets (13) and neuroendocrine cells or neurons (14) is well documented, there remains very little consensus in non-neuronal cell types.…”

Section: Discussionmentioning

confidence: 99%

“…Although the mechanism for ATP release is well established in platelets (13) and neurons/neuroendocrine cells (14), the mechanism by which nucleotides are released by non-neuronal cell types, including keratinocytes, remains controversial. Several postulated mechanisms exist, including ATP-binding cassette proteins (ABC proteins) (15)(16)(17)(18)(19)(20), which are in close proximity to P2 receptors (21), exocytotic vesicles (22-24), and cytolysis (25). Once released from the cell surface, nucleotides are quickly processed, providing a turnover of potential stimuli at P2 receptors.…”

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confidence: 99%

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Human Keratinocytes Release ATP and Utilize Three Mechanisms for Nucleotide Interconversion at the Cell Surface

Burrell

Wlodarski

Foster

et al. 2005

Journal of Biological Chemistry

111

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Nucleotide activation of P2 receptors is important in autocrine and paracrine regulation in many tissues. In the epidermis, nucleotides are involved in proliferation, differentiation, and apoptosis. In this study, we have used a combination of luciferin-luciferase luminometry, pharmacological inhibitors, and confocal microscopy to demonstrate that HaCaT keratinocytes release ATP into the culture medium, and that there are three mechanisms for nucleotide interconversion, resulting in ATP generation at the cell surface. Addition of ADP, GTP, or UTP to culture medium elevated the ATP concentration. ADP to ATP conversion was inhibited by diadenosine pentaphosphate, oligomycin, and UDP, suggesting the involvement of cell surface adenylate kinase, F 1 F 0 ATP synthase, and nucleoside diphosphokinase (NDPK), respectively, which was supported by immunohistochemistry. Simultaneous addition of ADP and GTP elevated ATP above that for each nucleotide alone indicating that GTP acts as a phosphate donor. However, the activity of NDPK, F 1 F 0 ATP synthase or the forward reaction of adenylate kinase could not fully account for the culture medium ATP content. We postulate that this discrepancy is due to the reverse reaction of adenylate kinase utilizing AMP. In normal human skin, F 1 F 0 ATP synthase and NDPK were differentially localized, with mitochondrial expression in the basal layer, and cell surface expression in the differentiated layers. We and others have previously demonstrated that keratinocytes express multiple P2 receptors. In this study we now identify the potential sources of extracellular ATP required to activate these receptors and provide better understanding of the role of nucleotides in normal epidermal homeostasis and wound healing.Extracellular nucleotides, such as ATP and ADP, are now recognized as important autocrine and paracrine factors involved in the regulation of many cellular processes in a wide range of tissues. They act via activation of the P2 family of receptors of which there are two subgroups: the P2X receptors (ligand-gated ion channels) and the P2Y receptors (G proteincoupled receptors) as determined by their molecular structure, transduction pathways, and pharmacological properties (1). There are currently seven members of the P2X subgroup (P2X 1-7 ) (2) and eight members of the P2Y subgroup (P2Y 1,2,4,6,11-14 ) identified in mammalian cell types (3).In the epidermis, P2 receptors are involved in the regulation of proliferation, differentiation, and apoptosis, and thus subtypes are expressed in different regions. Differential expression of multiple P2 receptor subtypes is species-and cell type-dependent (4 -7). Although P2Y 2 receptor expression is almost entirely confined to the proliferative basal layer (7, 8), P2X 5 receptors are expressed in keratinocytes in the early stages of differentiation, i.e. the spinous layer, and P2X 7 receptors are confined to the terminally differentiated cells of the cornified layer (8, 9). In vitro, normal human keratinocytes express mRNA for P2Y 1 , P2Y 2...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Human Keratinocytes Release ATP and Utilize Three Mechanisms for Nucleotide Interconversion at the Cell Surface

Burrell

Wlodarski

Foster

et al. 2005

Journal of Biological Chemistry

111

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“…The CFTR protein, in addition to its function as a Cl Ϫ channel, is able to modulate several cellular functions, including the regulation of epithelial Na ϩ channels (ENaC) (33), different types of Cl Ϫ channels (28,34,35), K ϩ channels (36), membrane recycling (37), and ATP release (38). The interaction of CFTR with other ion cotransporters has also been postulated (39).…”

Section: Discussionmentioning

confidence: 99%

Defective regulatory volume decrease in human cystic fibrosis tracheal cells because of altered regulation of intermediate conductance Ca ²⁺ -dependent potassium channels

Vázquez

Nobles

Valverde

2001

Proc. Natl. Acad. Sci. U.S.A.

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The cystic fibrosis transmembrane conductance regulator (CFTR) protein has the ability to function as both a chloride channel and a channel regulator. The loss of these functions explains many of the manifestations of the cystic fibrosis disease (CF), including lung and pancreatic failure, meconium ileus, and male infertility. CFTR has previously been implicated in the cell regulatory volume decrease (RVD) response after hypotonic shocks in murine small intestine crypts, an effect associated to the dysfunction of an unknown swelling-activated potassium conductance. In the present study, we investigated the RVD response in human tracheal CF epithelium and the nature of the volume-sensitive potassium channel affected. Neither the human tracheal cell line CFT1, expressing the mutant CFTR-⌬F508 gene, nor the isogenic vector control line CFT1-LC3, engineered to express the ␤gal gene, showed RVD. On the other hand, the cell line CFT1-LCFSN, engineered to express the wild-type CFTR gene, presented a full RVD. Patch-clamp studies of swelling-activated potassium currents in the three cell lines revealed that all of them possess a potassium current with the biophysical and pharmacological fingerprints of the intermediate conductance Ca 2؉ -dependent potassium channel (IK, also known as KCNN4). However, only CFT1-LCFSN cells showed an increase in IK currents in response to hypotonic challenges. Although the identification of the molecular mechanism relating CFTR to the hIK channel remains to be solved, these data offer new evidence on the complex integration of CFTR in the cells where it is expressed. CFTR ͉ ⌬F508 ͉ chloride secretion ͉ airways ͉ hIKK

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“…Although this regulatory function of CFTR is currently highly debated, 54 several additional laboratories have also noted that CFTR can facilitate ATP transport in a number of cell lines. [55][56][57] The added complexity of CFTR as a regulator of ATP transport in the airway has tremendous implications on potential mechanisms of interaction with other channels important in fluid and electrolyte balance.…”

Section: Cftr Is An Apical Membrane Chloride Channel and Regulator Ofmentioning

confidence: 99%

Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis

Jiang

Engelhardt

1998

Eur J Hum Genet

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Cystic fibrosis (CF) has become a paradigm disorder for the clinical testing of gene therapies in the treatment of inherited disease. In recent years, efforts directed at gene therapy of CF have concentrated on improving gene delivery systems to the airway. Surrogate endpoints for complementation of CFTR dysfunction in the lung have been primarily dependent on correction of chloride transport abnormalities. However, it is now clear that the pathophysiology of CF airways disease is far more complex than can be solely attributed to altered chloride permeability. For example, in addition to functioning as a chloride channel, CFTR also has been implicated in the regulation of other apical membrane conductance pathways through interactions with the amiloride sensitive epithelial sodium channel (ENaC) and the outwardly rectifying chloride channel (ORCC). Superimposed on this functional diversity of CFTR is a highly regulated pattern of CFTR expression in the lung. This heterogeneity occurs at both the level of CFTR protein expression within different cell types in the airway and the anatomical location of these cells in the lung. Potential targets for gene therapy of CF include ciliated, non-ciliated, and goblet cells in the surface airway epithelium as well as submucosal glands within the interstitium of the airways. Each of these distinct cellular compartments may have functionally distinct roles in processes which affect the pathogenesis of CF airways disease, such as fluid and electrolyte balance. However, it is presently unclear which of these cellular targets are most pathophysiologic relevant with regard to gene therapy. Elucidation of the underlying mechanisms of CFTR function in the airway will allow for the rational design of gene therapy approaches for CF lung diseases. This review will provide a summary of the field's current knowledge regarding CFTR functional diversity in the airway and the implications of such diversity for gene therapies of CF lung disease.

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Cellular ATP release by the cystic fibrosis transmembrane conductance regulator

Cited by 78 publications

References 20 publications

Human Keratinocytes Release ATP and Utilize Three Mechanisms for Nucleotide Interconversion at the Cell Surface

Human Keratinocytes Release ATP and Utilize Three Mechanisms for Nucleotide Interconversion at the Cell Surface

Defective regulatory volume decrease in human cystic fibrosis tracheal cells because of altered regulation of intermediate conductance Ca ²⁺ -dependent potassium channels

Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis

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Cellular ATP release by the cystic fibrosis transmembrane conductance regulator

Cited by 78 publications

References 20 publications

Human Keratinocytes Release ATP and Utilize Three Mechanisms for Nucleotide Interconversion at the Cell Surface

Human Keratinocytes Release ATP and Utilize Three Mechanisms for Nucleotide Interconversion at the Cell Surface

Defective regulatory volume decrease in human cystic fibrosis tracheal cells because of altered regulation of intermediate conductance Ca 2+ -dependent potassium channels

Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis

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Defective regulatory volume decrease in human cystic fibrosis tracheal cells because of altered regulation of intermediate conductance Ca ²⁺ -dependent potassium channels