title: MED1101: a new dialdehydic compound regulating P2×7 receptor cell surface expression in U937 cells.
abstract: BACKGROUND
  P2×7R is a member of the ionotropic family of purinergic receptors activated by millimolar concentrations of extracellular ATP such as induced by inflammatory stimuli. The receptor is widely expressed in cells of haematopoietic origin such as monocytes, macrophages and microglia. There is growing interest in anta-gonist compounds of the P2×7R since it has been demonstrated to be a viable therapeutic target for inflammatory diseases. Here, we tested the possible P2×7 antagonist effect of MED1101, a newly synthesised dialdehydic compound on U937 monocyte cells.
  
  
  RESULTS
  Human U937 cells express the full-length P2×7A receptor isoform. Treatment with lipopolysaccharide (LPS), a potent inducer of inflammation, significantly increased the expression of the receptor in the plasma membrane. Importantly, MED1101 induced internalisation of the P2×7R already after 30 min incubation in both physiological conditions and in presence of the inflammatory stimulus (LPS) and this effect was observable for up to 12 h after its removal. Moreover, MED1101 induced an impairment of monocyte migration/transmigration through direct P2×7R antagonism and subsequent inhibition of the intracellular signal transduction processes of Ca2+ influx and MAPK phosphorylation.
  
  
  CONCLUSIONS
  Our results clearly demonstrate that in U937 monocyte cells MED1101 acts as a P2×7R antagonist through the induction of receptor internalisation and subsequent inhibition of down-stream signal transduction pathways that regulate monocyte migration/transmigration, thus playing a potential therapeutic role in inflammatory diseases.
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, 70126, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Muzzachi
authors.forename: Antonella
authors.initials: A
authors.lastname: Blasi
authors.forename: Elena
authors.initials: E
authors.lastname: Ciani
authors.forename: Maria
authors.initials: M
authors.lastname: Favia
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Cardone
authors.forename: Domenico
authors.initials: D
authors.lastname: Marzulli
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Reshkin
authors.forename: Giulia
authors.initials: G
authors.lastname: Merizzi
authors.forename: Valeria
authors.initials: V
authors.lastname: Casavola
authors.forename: Antonio
authors.initials: A
authors.lastname: Soleti
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Guerra
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020298:U937 Cells
chemical_list: C580749:2-(1-(6-aminopurin-9-yl)-2-oxoethoxy)prop-2-enal; D000447:Aldehydes; D008070:Lipopolysaccharides; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D020928:Mitogen-Activated Protein Kinases; D000241:Adenosine; D002118:Calcium
keywords: Calcium signalling; Cell migration; Membrane protein; Purinergic receptors