title: Investigation of the role of sigma1-receptors in inositol 1,4,5-trisphosphate dependent calcium signaling in hepatocytes.
abstract: In hepatocytes, as in other cell types, Ca(2+) signaling is subject to complex regulations, which result largely from the intrinsic characteristics of the different inositol 1,4,5-trisphosphate receptor (InsP(3)R) isoforms and from their interactions with other proteins. Although sigma1 receptors (Sig-1Rs) are widely expressed in the liver, their involvement in hepatic Ca(2+) signaling remains unknown. We here report that in this cell type Sig-1R interact with type 1 isoforms of the InsP(3) receptors (InsP(3)R-1). These results obtained by immunoprecipitation experiments are confirmed by the observation that Sig-1R proteins and InsP(3)R-1 colocalize in hepatocytes. However, Sig-1R ligands have no effect on InsP(3)-induced Ca(2+) release in hepatocytes. This can be explained by the rather low expression level expression of InsP(3)R-1. In contrast, we find that Sig-1R ligands can inhibit agonist-induced Ca(2+) signaling via an inhibitory effect on InsP(3) synthesis. We show that this inhibition is due to the stimulation of PKC activity by Sig-1R, resulting in the well-known down-regulation of the signaling pathway responsible for the transduction of the extracellular stimulus into InsP(3) synthesis. The PKC sensitive to Sig-1R activity belongs to the family of conventional PKC, but the precise molecular mechanism of this regulation remains to be elucidated.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité UMR-S757, France.
authors.forename: A
authors.initials: A
authors.lastname: Abou-Lovergne
authors.forename: M
authors.initials: M
authors.lastname: Collado-Hilly
authors.forename: F P
authors.initials: FP
authors.lastname: Monnet
authors.forename: O
authors.initials: O
authors.lastname: Koukoui
authors.forename: S
authors.initials: S
authors.lastname: Prigent
authors.forename: J F
authors.initials: JF
authors.lastname: Coquil
authors.forename: G
authors.initials: G
authors.lastname: Dupont
authors.forename: L
authors.initials: L
authors.lastname: Combettes
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D005260:Female; D016257:Fura-2 / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000032:analysis / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010423:Pentazocine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D014667:Vasopressins / Q000494:pharmacology; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D016257:Fura-2; D015544:Inositol 1,4,5-Trisphosphate; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009638:Norepinephrine; D010423:Pentazocine; D011493:Protein Kinase C; D017480:Receptors, sigma; D014667:Vasopressins; D000097605:Sigma-1 Receptor