title: Down-regulation of GABA(A) receptor via promiscuity with the vasoactive peptide urotensin II receptor. Potential involvement in astrocyte plasticity.
abstract: GABA(A) receptor (GABA(A)R) expression level is inversely correlated with the proliferation rate of astrocytes after stroke or during malignancy of astrocytoma, leading to the hypothesis that GABA(A)R expression/activation may work as a cell proliferation repressor. A number of vasoactive peptides exhibit the potential to modulate astrocyte proliferation, and the question whether these mechanisms may imply alteration in GABA(A)R-mediated functions and/or plasma membrane densities is open. The peptide urotensin II (UII) activates a G protein-coupled receptor named UT, and mediates potent vasoconstriction or vasodilation in mammalian vasculature. We have previously demonstrated that UII activates a PLC/PIPs/Ca(2+) transduction pathway, via both G(q) and G(i/o) proteins and stimulates astrocyte proliferation in culture. It was also shown that UT/G(q)/IP(3) coupling is regulated by the GABA(A)R in rat cultured astrocytes. Here we report that UT and GABA(A)R are co-expressed in cerebellar glial cells from rat brain slices, in human native astrocytes and in glioma cell line, and that UII inhibited the GABAergic activity in rat cultured astrocytes. In CHO cell line co-expressing human UT and combinations of GABA(A)R subunits, UII markedly depressed the GABA current (β(3)γ(2)>α(2)β(3)γ(2)>α(2)β(1)γ(2)). This effect, characterized by a fast short-term inhibition followed by drastic and irreversible run-down, is not relayed by G proteins. The run-down partially involves Ca(2+) and phosphorylation processes, requires dynamin, and results from GABA(A)R internalization. Thus, activation of the vasoactive G protein-coupled receptor UT triggers functional inhibition and endocytosis of GABA(A)R in CHO and human astrocytes, via its receptor C-terminus. This UII-induced disappearance of the repressor activity of GABA(A)R, may play a key role in the initiation of astrocyte proliferation.
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Desrues
authors.forename: Thomas
authors.initials: T
authors.lastname: Lefebvre
authors.forename: Céline
authors.initials: C
authors.lastname: Lecointre
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Schouft
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leprince
authors.forename: Vincent
authors.initials: V
authors.lastname: Compère
authors.forename: Fabrice
authors.initials: F
authors.lastname: Morin
authors.forename: François
authors.initials: F
authors.lastname: Proust
authors.forename: Pierrick
authors.initials: P
authors.lastname: Gandolfo
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
authors.forename: Hélène
authors.initials: H
authors.lastname: Castel
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014579:Urotensins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D021122:Protein Subunits; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; C121697:UTS2R protein, human; D014579:Urotensins; C473142:Uts2r protein, rat; C029677:urotensin II; D002118:Calcium