Influx of Ca 2؉ ions through ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors contributes to neuronal damage in stroke, epilepsy, and neurodegenerative disorders such as ALS. The Ca 2؉ permeability of AMPA receptors is largely determined by the glutamate receptor 2 (GluR2) subunit, receptors lacking GluR2 being permeable to Ca 2؉ ions. We identified a difference in GluR2 expression in motor neurons from two rat strains, resulting in a difference in vulnerability to AMPA receptor-mediated excitotoxicity both in vitro and in vivo. Astrocytes from the ventral spinal cord were found to mediate this difference in GluR2 expression in motor neurons. The presence of ALS-causing mutant superoxide dismutase 1 in astrocytes abolished their GluR2-regulating capacity and thus affected motor neuron vulnerability to AMPA receptormediated excitotoxicity. These results reveal a mechanism through which astrocytes influence neuronal functioning in health and disease.amyotrophic lateral sclerosis ͉ ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor ͉ neurodegeneration ͉ mutant superoxide dismutase 1
We show here for the first time that HPC express VIPR2 and receive nerve endings. These features, and the fact that HPC numbers are influenced by the presence or absence of the autonomic innervation of the liver, suggest a direct interaction.
High-frequency electrical vagus stimulation improves portal hypertension in cirrhotic rats, most likely through release of VIP, binding to VIP receptor 2. As the technology is already in use for other applications, vagus nerve stimulation might be an important new strategy in the treatment of portal hypertension.
Background & Aims:We have previously shown that the hepatic vagus nerve stimulates the activation of hepatic progenitor cells (HPC), via muscarinic acetylcholine receptor type 3. Given the coproliferation of HPC and hepatic stellate cells (HSC) in acute hepatitis, we determined whether HSC proliferation is also modulated by vagal activity. Methods: We induced acute hepatitis in Wistar rats by injection of galactosamine and lipopolysaccharides. Hepatitis was preceded by hepatic branch vagotomy or sham vagotomy, by electrical stimulation or sham stimulation and by muscarinic receptor antagonist atropine, nicotinic receptor antagonist mecamylamine or saline injection. Rats were sacrificed after 12 and 48 h and HSC numbers were quantified on immunohistochemical stainings. Furthermore, we performed reverse transcriptase-polymerase chain reaction with receptor-specific primers on total RNA from isolated HSC and determined the in vitro proliferation of HSC in response to acetylcholine, atropine and mecamylamine. Results: HSC numbers were significantly lower after vagotomy than after sham vagotomy. Conversely, more HSC were seen after electrical stimulation than after sham stimulation. Atropine resulted in less HSC than saline at both time points, while mecamylamine treatment only diminished HSC after 12 h, suggesting a predominant involvement of muscarinic receptors. Moreover, HSC express muscarinic receptor type 2 mRNA and protein, as well as nicotinic receptor a1, a5, b1 and vasoactive intestinal peptide receptor 1 mRNA. Furthermore, acetylcholine enhanced the in vitro proliferation of HSC, which was inhibited by atropine, but not by mecamylamine. Conclusions: We show here that the hepatic vagus nerve stimulates HSC proliferation, most likely through binding of acetylcholine on muscarinic receptor type 2.
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