title: Sustained release of prostaglandin E₂ in fibroblasts expressing ectopically cyclooxygenase 2 impairs P2Y-dependent Ca²⁺-mobilization.
abstract: The nucleotide uridine trisphosphate (UTP) released to the extracellular milieu acts as a signaling molecule via activation of specific pyrimidine receptors (P2Y). P2Y receptors are G protein-coupled receptors expressed in many cell types. These receptors mediate several cell responses and they are involved in intracellular calcium mobilization. We investigated the role of the prostanoid PGE2 in P2Y signaling in mouse embryonic fibroblasts (MEFs), since these cells are involved in different ontogenic and physiopathological processes, among them is tissue repair following proinflammatory activation. Interestingly, Ca(2+)-mobilization induced by UTP-dependent P2Y activation was reduced by PGE2 when this prostanoid was produced by MEFs transfected with COX-2 or when PGE2 was added exogenously to the culture medium. This Ca(2+)-mobilization was important for the activation of different metabolic pathways in fibroblasts. Moreover, inhibition of COX-2 with selective coxibs prevented UTP-dependent P2Y activation in these cells. The inhibition of P2Y responses by PGE2 involves the activation of PKCs and PKD, a response that can be suppressed after pharmacological inhibition of these protein kinases. In addition to this, PGE2 reduces the fibroblast migration induced by P2Y-agonists such as UTP. Taken together, these data demonstrate that PGE2 is involved in the regulation of P2Y signaling in these cells.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Pimentel-Santillana
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain ; The Salk Institute, 10010 N Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Paqui G
authors.initials: PG
authors.lastname: Través
authors.affiliation: Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria e Instituto Universitario de Investigación en Neuroquímica, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pérez-Sen
authors.affiliation: Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria e Instituto Universitario de Investigación en Neuroquímica, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain.
authors.forename: Esmerilda G
authors.initials: EG
authors.lastname: Delicado
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.affiliation: Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria e Instituto Universitario de Investigación en Neuroquímica, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain ; Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria e Instituto Universitario de Investigación en Neuroquímica, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D007118:Immunoassay; D051379:Mice; D008810:Mice, Inbred C57BL; D058470:Receptors, Purinergic P2Y / Q000378:metabolism*
chemical_list: D058470:Receptors, Purinergic P2Y; D051546:Cyclooxygenase 2; D002118:Calcium