title: Effect of GABA A receptor activation on UT-coupled signaling pathways in rat cortical astrocytes.
abstract: Cultured rat cortical astrocytes express two types of urotensin II (UII) binding sites: a high affinity site corresponding to the UT (GPR14) receptor and a low affinity site that has not been fully characterized. Activation of the high affinity site in astroglial cells stimulates polyphosphoinositide (PIP) turnover and provokes an increase in intracellular calcium concentration. We have hypothesized that the existence of distinct affinity sites for UII in rat cortical astrocytes could be accounted for by a possible cross-talk between UT and the ligand-gated ion channel GABA(A) receptor (GABA A R). Exposure of cultured astrocytes to UII provoked a bell-shaped increase in cAMP production, with an EC50 stimulating value of 0.83+/-0.04 pM, that was totally blocked in the presence of the adenylyl cyclase inhibitor SQ 22,536. In contrast, UII was found to inhibit forskolin-induced cAMP formation. In the presence of the specific PKA inhibitor H89, UII provoked a sustained stimulation of cAMP formation. Inhibition of PKA by H89 strongly reduced the stimulatory effect of UII on PIP metabolism. GABA and the GABA A R agonist isoguvacine provoked a marked inhibition of UII-induced cAMP synthesis and a significant reduction of UII-evoked PIP turnover. These data suggest that functional interaction between UT and GABA(A)R negatively regulates coupling of UT to the classical PLC/IP(3) signaling cascade as well as to the adenylyl cyclase/PKA pathway.
authors: INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, 76821 Mont-Saint-Aignan, France.
authors: Laurence
authors: L
authors: Desrues
authors: Thomas
authors: T
authors: Lefebvre
authors: Mickaël
authors: M
authors: Diallo
authors: Pierrick
authors: P
authors: Gandolfo
authors: Jérôme
authors: J
authors: Leprince
authors: David
authors: D
authors: Chatenet
authors: Hubert
authors: H
authors: Vaudry
authors: Marie-Christine
authors: MC
authors: Tonon
authors: Hélène
authors: H
authors: Castel
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005576:Colforsin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D018755:GABA Agonists / Q000378:metabolism; D007539:Isonicotinic Acids / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013004:Somatostatin / Q000378:metabolism; D014579:Urotensins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D018755:GABA Agonists; D007539:Isonicotinic Acids; D010716:Phosphatidylinositols; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D014579:Urotensins; C017759:9-(tetrahydro-2-furyl)-adenine; D005576:Colforsin; D013004:Somatostatin; C029677:urotensin II; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000225:Adenine; C015300:isoguvacine