Interaction of prostaglandin E2 and β-adrenergic catecholamines in the regulation of uterine smooth muscle motility and adenylate cyclase in the rat

Abstract

Prostaglandin E2 (PGE2) increased the force of the spontaneous contractions of the rat myometrium and decreased the sensitivity of the uterus to the relaxing effects of the specific beta-adrenergic catecholamine agonist isoprenaline. Prostaglandin E2, at concentrations above 10 mumol/l, increased cyclic AMP production by intact muscle strips. The muscle strips were far more sensitive, however, to the inhibitory effect PGE2 had on isoprenaline-dependent cyclic AMP production (threshold less than 0.001 nmol/l). Both PGE2 and isoprenaline stimulated adenylate cyclase activity of a myometrial subcellular (particulate) fraction in a guanyl nucleotide-requiring manner. When present in saturating concentrations (100 mumol/l), the stimulatory effects were not additive, suggesting that the receptors for the two agonists competed for the same catalytic subunit of adenylate cyclase or for the same guanyl nucleotide-requiring factor which couples receptors and enzyme. If muscle strips were incubated with PGE2 before the preparation of the adenylate cyclase-containing particulate fraction, the enzyme became less responsive to stimulation by guanyl nucleotide and by isoprenaline and PGE2 in the presence of guanyl nucleotide. The PGE2 receptor may therefore interact with the beta-adrenoreceptor to inhibit isoprenaline-dependent cyclic AMP production by intact muscle cells by desensitizing adenylate cyclase, possibly at the level of the guanyl nucleotide-dependent coupling step.

The C‐terminal domain of the Gs‐coupled EP4 receptor confers agonist‐dependent coupling control to Gi but no coupling to Gs in a receptor hybrid with the Gi‐coupled EP3 receptor

“…In the current study the C-terminal domain of the G scoupled I1EP4R was not able to shift the Gj-coupled rEP 3 ßR to a G s -coupled receptor or to confer an additional G s coupling. In contrast, the chimeric rEP 3 hEP 4 R not only retained its rEP 3 ßR binding profile but also its Gj coupling properties.…”

“…Prostaglandin E2 (PGE 2 ) is a potent mediator of physiological and pathophysiological events in the body, for example stimulation of neurotransmitter release, regulation of the immune system and uterus contraction [1][2][3]. Its actions are mediated by binding to specific PGE2 ectoreceptors (EPR), »Corresponding author.…”

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

“…PGE receptors are pharmacologically subdivided into four subtypes, EP1, EP2, EP3, and EP4, on the basis of their responses to various agonists and antagonists [2,3]. Among these subtypes, the EP3 receptor has been best characterized; it has been suggested to be involved in such PGE2 actions as contraction of the uterus [4], inhibition of gastric acid secretion [5], modulation of the neurotransmitter release [6], lipolysis in adipose tissue [7], and sodium and water reabsorption in the kidney tubules [8]. Various EP3 receptor-mediated actions are mediated through multiple signal transduction systems, and in addition, the doseresponse curve and potency of PGE2 vary with tissue, implying heterogeneity of EP3 receptors [9,10].…”

Immunohistochemical localization of prostaglandin EP3 receptor in the rat nervous system

“…Those studies contributed to an explanation of the PG production mechanism in the CNS, whereas histochemical approaches to the PGE receptors have almost never been performed. Among the PGE receptor subtypes, the EP3 receptor (EP3R) has been the best characterized and has been reported to be involved in contraction of the uterus (Krall et al, 1984), inhibition of gastric acid secretion (Chen et al, 1988), lipolysis in the adipose tissue (Richelsen and Beck-Nielsen, 1984), and sodium and water reabsorption in the kidney tubules (Garcia-Perez and Smith, 1984). These various actions of EP3R have been thought to be induced by inhibition of adenylate cyclase or stimulation of Ca 2ϩ mobilization (Negishi et al, 1995).…”