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HORMONES AND SIGNALING

Effects of the prostaglandins PGF₂ and PGE₂ on calcium signaling in rat hepatocyte doublets

¹Institut National de la Santé et de la Recherche Médicale Unité 442, Université Paris-Sud, Orsay, France; and ²Laboratoire de Pharmacologie et d'Hormonologie, Institut des Sciences Biomédicales Appliquées, Cotonou, Bénin

Submitted 24 February 2005 ; accepted in final form 29 July 2005

Coordination of intercellular Ca²⁺ signals is important for certain hepatic functions including biliary flow and glucose output. Prostaglandins, such as PGF₂ and PGE₂, may modify these hepatocyte functions by inducing Ca²⁺ increase, but very little is known about the organization of the Ca²⁺ signals induced by these agonists. We studied Ca²⁺ signals induced by PGF₂ and PGE₂ in fura-2 AM-loaded hepatocyte doublets. Even though both prostaglandins induced Ca²⁺ oscillations, neither PGF₂ nor PGE₂ induced coordinated Ca²⁺ oscillations in hepatocyte doublets. Gap junction permeability (GJP), assessed by fluorescence recovery after photobleaching, showed that this absence of coordination was not related to a defect in GJP. Inositol (1,4,5)trisphosphate [Ins(1,4,5)P₃] assays and the increase in Ins(1,4,5)P₃ receptor sensitivity to Ins(1,4,5)P₃ observed in response to thimerosal suggested that the absence of coordination was a consequence of the very small quantity of Ins(1,4,5)P₃ formed by these prostaglandins. Furthermore, when PGE₂ and PGF₂ were added just before norepinephrine, they favored the coordination of Ca²⁺ signals induced by norepinephrine. However, GJP between hepatocyte doublets was strongly inhibited by prolonged (2 h) treatment with PGF₂, thereby preventing the coordination of Ca²⁺ oscillations induced by norepinephrine in these cells. Thus, depending on the time window, prostaglandins, specially PGF₂, may enhance or diminish the propagation of Ca²⁺ signals. They may therefore contribute to the fine tuning of Ca²⁺ wave-dependent functions, such as nerve stimulation, hormonal regulation of liver metabolism, or bile secretion, in both normal and pathogenic conditions.

calcium oscillations; gap junction permeability