Abstract
GABAA receptor (GABAAR) expression level is inversely correlated with the proliferation rate of astrocytes after stroke or during malignancy of astrocytoma, leading to the hypothesis that GABAAR 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 GABAAR-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/Ca2+ transduction pathway, via both Gq and Gi/o proteins and stimulates astrocyte proliferation in culture. It was also shown that UT/Gq/IP3 coupling is regulated by the GABAAR in rat cultured astrocytes. Here we report that UT and GABAAR 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 GABAAR subunits, UII markedly depressed the GABA current (β3γ2>α2β3γ2>α2β1γ2). 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 Ca2+ and phosphorylation processes, requires dynamin, and results from GABAAR internalization. Thus, activation of the vasoactive G protein-coupled receptor UT triggers functional inhibition and endocytosis of GABAAR in CHO and human astrocytes, via its receptor C-terminus. This UII-induced disappearance of the repressor activity of GABAAR, may play a key role in the initiation of astrocyte proliferation.
Highlights
Integrated brain function and dysfunction arise from the complex interactions between a network of multiple cell types including neurons, c and the microvascular endothelial cells comprising the cerebral vasculature [1,2,3]
MRNA encoding the vasoactive receptor UT are detected in the olfactory system, hippocampus, amygdala, tegmental nuclei, or cerebellum [27,65,66] and urotensin II (UII) binding sites are restricted to few areas including the cerebellar cortex [39,67]
We showed intense UT labeling in Purkinje cell bodies and ramifications as well as in glial BergmannGFAP positive long processes where it co-localizes with c1 and, to a lesser extent, with c2 subunits of the GABAA receptor (GABAAR), and in astrocytes co-cultured with granule neurons
Summary
Integrated brain function and dysfunction arise from the complex interactions between a network of multiple cell types including neurons, c and the microvascular endothelial cells comprising the cerebral vasculature [1,2,3]. A significant decrease of benzodiazepine sites associated to the GABAAR has been demonstrated in patients with ischemic cerebrovascular [15,16,17], Parkinson [18] and Alzheimer [19,20] diseases It was observed a reduced chloride conductance [21], a decrease in receptor mediated inhibitory post-synaptic potentials [22] and a marked down-regulation of the GABAAR expression at the cell surface along with a fast time course [15,23,24]. As many neurotransmitters and vasoactive peptides are released by endothelium and astrocytes, and their receptors are expressed by astrocytes, there is a potential for complex signaling within the neurovascular unit, involving receptor cross-talks
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