title: Potentiation of ATP- and bradykinin-induced [Ca2+]c responses by PTHrP peptides in the HaCaT cell line.
abstract: In the epidermis, local and systemic factors including extracellular nucleotides and parathyroid hormone-related protein (PTHrP) regulate keratinocyte proliferation and differentiation. Extracellular nucleotides increase proliferation via activation of P2 receptors and induction of calcium transients, while endoproteases cleave PTHrP, resulting in fragments with different cellular functions. We investigated the effects of adenosine 5'-triphosphate (ATP) alone and in combination with synthetic PTHrP peptides on calcium transients in HaCaT cells. ATP induced calcium transients, while PTHrP peptides did not. C-terminal and mid-molecule PTHrP peptides (1-100 pM) potentiated ATP-induced calcium transients independently of calcium influx. 3-Isobutyl-1-methylxanthine potentiated ATP-induced calcium transients, suggesting that a cyclic monophosphate is responsible. Cyclic AMP is not involved, but cyclic GMP is a likely candidate since the protein kinase G inhibitor, KT5823, inhibited potentiation. Co-stimulation with ATP and either PTHrP (43-52) or PTHrP (70-77) increased proliferation, suggesting that this is important in the regulation of cell turnover and wound healing and may be a mechanism for hyperproliferation in skin disorders such as psoriasis. Finally, PTHrP fragments potentiated bradykinin-induced calcium transients, suggesting a role in inflammation in the skin. Since PTHrP is found in many normal and malignant cells, potentiation is likely to have a wider role in modulating signal transduction events.
authors.affiliation: Department of Human Anatomy and Cell Biology, University of Liverpool, Liverpool, UK. H.Burrell@ljmu.ac.uk
authors.forename: Helen E
authors.initials: HE
authors.lastname: Burrell
authors.forename: Alec W M
authors.initials: AW
authors.lastname: Simpson
authors.forename: Sharonpreet
authors.initials: S
authors.lastname: Mehat
authors.forename: David T
authors.initials: DT
authors.lastname: McCreavy
authors.forename: Brian
authors.initials: B
authors.lastname: Durham
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.forename: Graham R
authors.initials: GR
authors.lastname: Sharpe
authors.forename: James A
authors.initials: JA
authors.lastname: Gallagher
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002227:Carbazoles; D007211:Indoles; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; C073601:KT 5823; D005576:Colforsin; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D006152:Cyclic GMP; D001920:Bradykinin; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine