Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells.
PGE(2) and PGI(2) stimulate renin secretion and cAMP accumulation in juxtaglomerular granular (JG) cells. We addressed, at the single-cell level, the receptor subtypes and intracellular transduction mechanisms involved. Patch clamp was used to determine cell capacitance (C(m)), current, and membrane voltage in response to PGE(2), EP2 and EP4 receptor agonists, and an IP receptor agonist. PGE(2) (0.1 micromol/l) increased C(m) significantly, and the increase was abolished by intracellular application of the protein kinase A antagonist Rp-8-CPT-cAMPS. EP2-selective ligands butaprost (1 micromol/l), AE1-259-01 (1 nmol/l), EP4-selective agonist AE1-329 (1 nmol/l), and IP agonist iloprost (1 micromol/l) significantly increased C(m) mediated by PKA. The EP4 antagonist AE3-208 (10 nmol/l) blocked the effect of EP4 agonist but did not alter the response to PGE(2). Application of both EP4 antagonist and EP2-antagonist AH-6809 abolished the effects of PGE(2) on C(m) and current. EP2 and EP4 ligands stimulated cAMP formation in JG cells. PGE(2) rapidly stimulated renin secretion from superfused JG cells and diminished the membrane-adjacent granule pool as determined by confocal microscopy. The membrane potential hyperpolarized significantly after PGE(2), butaprost, AE1-329 and AE1-259 and outward current was augmented in a PKA-dependent fashion. PGE(2)-stimulated outward current, but not C(m) change, was abolished by the BK(Ca) channel inhibitor iberiotoxin (300 nmol/l). EP2 and EP4 mRNA was detected in sampled JG cells, and the preglomerular and glomerular vasculature was immunopositive for EP4. Thus IP, EP2, and EP4 receptors are associated with JG cells, and their activation leads to rapid PKA-mediated exocytotic fusion and release of renin granules.
Friis
Ulla G
UG
Dept. of Physiology and Pharmacology, University of Southern Denmark, DK-5000 Odense C, Denmark.
Stubbe
Jane
J
Uhrenholt
Torben R
TR
Svenningsen
Per
P
Nüsing
Rolf M
RM
Skøtt
Ole
O
Jensen
Boye L
BL
D000818:Animals; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005089:Exocytosis; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012083:Renin / Q000493:pharmacokinetics*
D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D012083:Renin