Autocrine regulation of wound healing by ATP release and P2Y2 receptor activation

Autocrine regulation of wound healing by ATP release and P2Y2 receptor activation

Application of exogenous nucleotides can modulate wound healing via the activation of purinergic receptors. However, evidence for the release of endogenous nucleotides and the subsequent activation of purinergic receptors in this process has not been well defined. Therefore, the current study aimed...

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Bibliographic Details
Published in:Life sciences (1973) Vol. 283; p. 119850
Main Authors: McEwan, T.B.-D., Sophocleous, R.A., Cuthbertson, P., Mansfield, K.J., Sanderson-Smith, M.L., Sluyter, R.
Format: Journal Article
Language:English
Published: New York Elsevier Inc 15-10-2021
Elsevier BV
Subjects:
Adenosine
Adenosine triphosphate
Apyrase
ATP
Autocrine signalling
Calcium (extracellular)
Calcium (intracellular)
Calcium antagonists
Calcium ions
Calcium release channels
Ectonucleotidase
Extracellular ATP
Immunoblotting
Immunomodulation
In vitro methods and tests
Inositol 1,4,5-trisphosphate receptors
Intracellular
Keratinocyte
Modulators
Nucleotides
Phospholipase C
Purine P2 receptors
Purine P2Y receptors
Purine receptors
Purinergic receptor
Receptor mechanisms
Receptors
Scratching
Signal transduction
Signaling
Skin
Suramin
Uridine
Wound closure
Wound healing
Keratinocyte
Skin
Extracellular ATP
Purinergic receptor
Wound closure
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Summary:Application of exogenous nucleotides can modulate wound healing via the activation of purinergic receptors. However, evidence for the release of endogenous nucleotides and the subsequent activation of purinergic receptors in this process has not been well defined. Therefore, the current study aimed to investigate wound-mediated nucleotide release and autocrine purinergic signalling during HaCaT keratinocyte wound closure following scratch injury. An in vitro scratch wound apparatus was employed to study wound healing over 24-h in the presence of modulators of ATP release, P2 receptors and pathways downstream of P2 receptor activation. Adenosine 5′-triphosphate (ATP) was released from scratched cells. The ectonucleotidase apyrase and pharmacological inhibition of the nucleotide release hemichannel, pannexin-1, decreased wound closure over time. The non-selective P2Y receptor antagonist suramin and the selective P2Y2 receptor antagonist AR-C118925XX, but not other P2 antagonists, decreased wound closure. AR-C118925XX decreased wound closure in a concentration-dependent fashion. However, exogenous P2Y2 receptor agonists, ATP or uridine 5′-triphosphate, did not enhance wound closure. PCR and immunoblotting confirmed P2Y2 receptor expression in HaCaT cells. U73122, a phospholipase C antagonist, and 2-aminoethoxydiphenylborate, an inositol 1,4,5-trisphosphate receptor-sensitive Ca2+-release channel antagonist, decreased wound closure consistent with P2Y2 receptor activation. Absence of extracellular or intracellular Ca2+ or inhibition of intracellular Ca2+-release also impaired wound closure. These data describe a novel autocrine signalling mechanism in which wound-mediated release of endogenous ATP in response to mechanical scratching of HaCaT cells activates P2Y2 receptors to facilitate wound closure. [Display omitted]
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ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2021.119850