Role of Extracellular Adenosine Triphosphate in Human Skin

Holzer, Aton M.; Granstein, Richard D.

doi:10.1007/s10227-004-0125-5

Cited by 12 publications

(13 citation statements)

References 124 publications

(83 reference statements)

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“…In physiological and in pathological conditions, many kind of cells related to nervous and immune systems, can generate ATP extravasation and accumulation in the extracellular medium of keratinocytes. Two important functions are attributed to this nucleotide such as modulation of keratinocyte proliferation and differentiation [110]. Many studies have shown that these effects are mediated by ATP action through P2X and P2Y receptor subtypes, and it is known that the epidermis expresses P2X5, P2X7, P2Y1, and P2Y2 subtypes with diverse functions [111][112][113].…”

Section: Skin Injurymentioning

confidence: 99%

“…In an in vivo wound-healing model, the P2Y1 receptor is expressed in epidermal basal layers and the wound edge, while the P2Y2 subtype is expressed in basal and suprabasal layers, but is not expressed in the wound edge. Alterations of distribution patterns of purinergic receptors occur during phenotype changes as keratinocytes become migratory cells in the wound-healing process [110]. P2X5 receptors are expressed in undifferentiated basal and intermediate layers of fetal epidermis with high immunoreactivity for cytokeratin-10, an initial differentiation marker [111].…”

Section: Skin Injurymentioning

confidence: 99%

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Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

Glaser

Cappellari

Pillat

et al. 2011

Purinergic Signalling

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Replacement of lost or dysfunctional tissues by stem cells has recently raised many investigations on therapeutic applications. Purinergic signaling has been shown to regulate proliferation, differentiation, cell death, and successful engraftment of stem cells originated from diverse origins. Adenosine triphosphate release occurs in a controlled way by exocytosis, transporters, and lysosomes or in large amounts from damaged cells, which is then subsequently degraded into adenosine. Paracrine and autocrine mechanisms induced by immune responses present critical factors for the success of stem cell therapy. While P1 receptors generally exert beneficial effects including anti-inflammatory activity, P2 receptor-mediated actions depend on the subtype of stimulated receptors and localization of tissue repair. Pro-inflammatory actions and excitatory tissue damages mainly result from P2X7 receptor activation, while other purinergic receptor subtypes participate in proliferation and differentiation, thereby providing adequate niches for stem cell engraftment and novel mechanisms for cell therapy and endogenous tissue repair. Therapeutic applications based on regulation of purinergic signaling are foreseen for kidney and heart muscle regeneration, Clara-like cell replacement for pulmonary and bronchial epithelial cells as well as for induction of neurogenesis in case of neurodegenerative diseases.

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Section: Skin Injurymentioning

confidence: 99%

Section: Skin Injurymentioning

confidence: 99%

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

Glaser

Cappellari

Pillat

et al. 2011

Purinergic Signalling

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“…This network plays important roles in both physiology and pathophysiology, and as such is an emerging therapeutic target to combat many diseases [3] . Evidence indicates that the extracellular nucleotide adenosine triphosphate (ATP) and cell surface purinergic receptors and ecto-nucleotidases play important roles in skin biology [4,5] . Within this context the P2X7 receptor has a major role.…”

Section: Overviewmentioning

confidence: 99%

“…Extracellular ATP or other nucleotides can subsequently lead to activation of two purinergic P2 receptor subtypes; P2X and P2Y receptors. P2X receptors are a family of seven trimeric ATP-gated cation channels (P2X1-7); while P2Y receptors are a group of eight G protein-coupled receptors (P2Y1, 2, 4,6,[11][12][13][14]. P2 receptors are expressed on numerous cell subtypes, and activation of these receptors by extracellular ATP, or other nucleotides for some receptor subtypes, are important in inflammation and immunity [7] .…”

Section: Purinergic Signallingmentioning

confidence: 99%

P2X7 receptor in skin biology and diseases

Geraghty¹,

Watson²,

Adhikary³

et al. 2016

WJD

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The P2X7 receptor is a trimeric ligand-gated cation channel present on immune and other cells. Activation of this receptor by its natural ligand extracellular adenosine triphosphate results in a variety of downstream responses, including the release of pro-inflammatory mediators and cell death. In normal skin, P2X7 is present on keratinocytes, Langerhans cells and fibroblasts, while the presence of this receptor on other cutaneous cells is mainly inferred from studies of equivalent cell types present in other tissues. Mast cells in normal skin however express negligible amounts of P2X7, which can be upregulated in cutaneous disease. This review discusses the potential significance of P2X7 in skin biology, and the role of this receptor in inflammatory skin disorders such as irritant and chronic dermatitis, psoriasis, graft-versus-host disease, as well is in wound healing, transplantation and skin cancer. AbstractThe P2X7 receptor is a trimeric ligand-gated cation channel present on immune and other cells. Activation of this receptor by its natural ligand extracellular adenosine triphosphate results in a variety of downstream responses, including the release of pro-inflammatory mediators and cell death. In normal skin, P2X7 is present on keratinocytes, Langerhans cells and fibroblasts, while the presence of this receptor on other cutaneous cells is mainly inferred from studies of equivalent cell types present in other tissues. Mast cells in normal skin however express negligible amounts of P2X7, which can be upregulated in cutaneous disease. This review discusses the potential significance of P2X7 in skin biology, and the role of this receptor in inflammatory skin disorders such as irritant and chronic dermatitis, psoriasis, graft-versus-host disease, as well is in wound healing, transplantation and skin cancer. Core tip: The P2X7 receptor is present on immune, stromal and epithelial cells. Activation of this receptor by its natural ligand, extracellular adenosine triphosphate, causes a variety of downstream effects including release of inflammatory mediators and growth factors, as well as cell death. P2X7 has various functions on skin cells, and studies of mouse models of disease and of human cells and tissues highlight emerging roles for this receptor in common skin disorders.

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“…Extracellular nucleotides are also released at micromolar concentrations in the wound bed (Lazarowski et al, 2003;Holzer and Granstein, 2004;Burrell et al, 2003;Yin et al, 2007). At these concentrations, extracellular nucleotides activate two classes of purinergic receptors: the Gprotein-coupled receptors (P2Y) and the ATP-gated ion channels (P2X) (Burnstock, 2007).…”

Section: Introductionmentioning

confidence: 99%

P2Y2 receptor inhibits EGF-induced MAPK pathway to stabilise keratinocyte hemidesmosomes.

Faure

Garrouste

Parat

et al. 2012

Journal of Cell Science

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Summary a6b4 integrin is the main component of hemidesmosomes (HD) that stably anchor the epithelium to the underlying basement membrane. Epithelial cell migration requires HD remodelling, which can be promoted by epidermal growth factor (EGF). We previously showed that extracellular nucleotides inhibit growth factor-induced keratinocyte migration. Here, we investigate the effect of extracellular nucleotides on a6b4 integrin localisation in HD during EGF-induced cell migration. Using a combination of pharmacological inhibition and gene silencing approaches, we found that UTP activates the P2Y2 purinergic receptor and Gaq protein to inhibit EGF/ERK1/2-induced cell migration in keratinocytes. Using a keratinocyte cell line expressing an inducible form of the Raf kinase, we show that UTP inhibits the EGF-induced ERK1/2 pathway activation downstream of Raf. Moreover, we established that ERK1/2 activation by EGF leads to the mobilisation of a6b4 integrin from HD. Importantly, activation of P2Y2R and Gaq by UTP promotes HD formation and protects these structures from EGF-triggered dissolution as revealed by confocal analysis of the distribution of a6b4 integrin, plectin, BPAG1, BPAG2 and CD151 in keratinocytes. Finally, we demonstrated that the activation of p90RSK, downstream of ERK1/2, is sufficient to promote EGF-mediated HD dismantling and that UTP does not stabilise HD in cells expressing an activated form of p90RSK. Our data underline an unexpected role of P2Y2R and Gaq in the inhibition of the ERK1/2 signalling pathway and in the modulation of hemidesmosome dynamics and keratinocyte migration.

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Role of Extracellular Adenosine Triphosphate in Human Skin

Abstract: Extracellular ATP seems to play a direct role in triggering skin inflammatory, regenerative, and fibrotic responses to mechanical injury, an indirect role in melanocyte proliferation and apoptosis, and a complex role in Langerhans cell-directed adaptive immunity.

Cited by 12 publications

References 124 publications

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

P2X7 receptor in skin biology and diseases

P2Y2 receptor inhibits EGF-induced MAPK pathway to stabilise keratinocyte hemidesmosomes.

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