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Increased potency of 1-adrenergic receptors to induce inositol phosphates production correlates with the up-regulation of 1d/Gh/phospholipase C1 signaling pathway in term rat myometrium

CNRS UMR 7079, Laboratoire de Physiologie et Physiopathologie, 75231 Paris Cedex 05, France and¹ INRA UMR 1054, Unité de Neuro-Gastroentérologie and Nutrition, 31931 Toulouse Cedex 09, France

Correspondence should be addressed to S Mhaouty-Kodja who is now at CNRS UMR 7148, Collège de France, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France; Email: sakina.mhaouty-kodja{at}college-de-france.fr

In the present study, we studied the potential regulation by rat myometrial 1-adrenergic receptors (1-AR) of the newly identified Gh protein/phospholipase C1 (PLC1) signaling pathway and compared myometrial inositol phosphates (InsP) production and activity of the uterine circular muscle in response to 1-AR activation between mid-pregnancy and term. For this, we quantified the level of rat myometrial 1-AR coupling to Gh protein by photoaffinity-labeling, the cytosolic amount of PLC1 enzyme by immunoblotting, and the expression level of 1-AR subtypes by RT-PCR. The results showed an increased level of 1-AR/Gh protein coupling and the amount of PLC1 at term (+147 and +65% respectively, versus mid-pregnancy). This was correlated with an up-regulation of 1d-AR subtype (+70% versus mid-pregnancy). Incubation of myometrial strips with phenylephrine (Phe), a global 1-agonist, increased InsP production in a dose-dependent manner at both mid-pregnancy and term, but with an enhanced potency (tenfold decrease in EC₅₀ value) at term. Phe also dose-dependently induced contraction of the circular muscle at both mid-pregnancy and term. However, unlike InsP response, no amelioration of potency was observed at term. Similar results were obtained with the endogenous agonist norepinephrine. Our results show, for the first time, that rat myometrial 1d-AR/Gh/PLC1 signaling pathway is up-regulated at term. This is associated with an increased potency of 1-AR to elicit InsP production but not uterine contraction at this period. It is thus hypothesized that 1-AR, through activation of Gh/PLC1 system, are not primarily involved in the initiation of labor but may rather regulate responses such as myometrial cell proliferation or hypertrophy.