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Neuronal activity in the retina generates osmotic gradients that lead to Müller cell swelling, followed by a regulatory volume decrease (RVD) response, partially due to the isoosmotic efflux of KCl and water. However, our previous studies in a human Müller cell line (MIO-M1) demonstrated that an important fraction of RVD may also involve the efflux of organic solutes. We also showed that RVD depends on the swelling-induced Ca 2+  release from intracellular stores. Here we investigate the contribution of taurine (Tau) and glutamate (Glu), the most relevant amino acids in Müller cells, to RVD through the volume-regulated anion channel (VRAC), as well as their Ca 2+  dependency in MIO-M1 cells. Swelling-induced [ 3 H]Tau/[ 3 H]Glu release was assessed by radiotracer assays and cell volume by fluorescence videomicroscopy. Results showed that cells exhibited an osmosensitive efflux of [ 3 H]Tau and [ 3 H]Glu (Tau &gt; Glu) blunted by VRAC inhibitors 4-(2-butyl-6,7-dichloro-2-cyclopentylindan-1-on-5-yl)-oxybutyric acid and carbenoxolone reducing RVD. Only [ 3 H]Tau efflux was mainly dependent on Ca 2+  release from intracellular stores. RVD was unaffected in a Ca 2+ -free medium, probably due to Ca 2+ -independent Tau and Glu release, but was reduced by chelating intracellular Ca 2+ . The inhibition of phosphatidylinositol-3-kinase reduced [ 3 H]Glu efflux but also the Ca 2+ -insensitive [ 3 H]Tau fraction and decreased RVD, providing evidence of the relevance of this Ca 2+ -independent pathway. We propose that VRAC-mediated Tau and Glu release has a relevant role in RVD in Müller cells. The observed disparities in Ca 2+  influence on amino acid release suggest the presence of VRAC isoforms that may differ in substrate selectivity and regulatory mechanisms, with important implications for retinal physiology.    NEW &amp; NOTEWORTHY The mechanisms for cell volume regulation in retinal Müller cells are still unknown. We show that swelling-induced taurine and glutamate release mediated by the volume-regulated anion channel (VRAC) largely contributes the to the regulatory volume decrease response in a human Müller cell line. Interestingly, the hypotonic-induced efflux of these amino acids exhibits disparities in Ca 2+ -dependent and -independent regulatory mechanisms, which strongly suggests that Müller cells may express different VRAC heteromers formed by the recently discovered leucine-rich repeat containing 8 (LRRC8) proteins.

Release of taurine and glutamate contributes to cell volume regulation in human retinal Müller cells: differences in modulation by calcium