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ASIC1a senses lactate uptake to regulate metabolism in neurons
- Source :
- Redox Biology, Vol 51, Iss , Pp 102253- (2022)
- Publication Year :
- 2022
- Publisher :
- Elsevier, 2022.
-
Abstract
- Lactate is a major metabolite largely produced by astrocytes that nourishes neurons. ASIC1a, a Na+ and Ca2+-permeable channel with an extracellular proton sensing domain, is thought to be activated by lactate through chelation of divalent cations, including Ca2+, Mg2+ and Zn2+, that block the channel pore. Here, by monitoring lactate-evoked H+ and Ca2+ transport in cultured mouse cortical and hippocampal neurons, we find that stereo-selective neuronal uptake of L-lactate results in rapid intracellular acidification that triggers H+ extrusion to activate plasma membrane ASIC1a channels, leading to propagating Ca2+ waves into the cytosol and mitochondria. We show that lactate activates ASIC1a at its physiological concentrations, far below that needed to chelate divalent cations. The L-isomer of lactate exerts a much greater effect on ASIC1a-mediated activity than the d-isomer and this stereo-selectivity arises from lactate transporters, which prefer the physiologically common L-lactate. The lactate uptake in turn results in intracellular acidification, which is then followed by a robust acid extrusion. The latter response sufficiently lowers the pH in the vicinity of the extracellular domain of ASIC1a to trigger its activation, resulting in cytosolic and mitochondrial Ca2+ signals that accelerate mitochondrial respiration. Furthermore, blocking ASIC1a led to a robust mitochondrial ROS production induced by L-lactate. Together our results indicate that ASIC1a is a metabolic sensor, which by sensing extracellular pH drop triggered by neuronal lactate uptake with subsequent proton extrusion, transmits a Ca2+ response that is propagated to mitochondria to enhance lactate catabolism and suppress ROS production.
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 51
- Issue :
- 102253-
- Database :
- Directory of Open Access Journals
- Journal :
- Redox Biology
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.b926e1d3e12f4f24bca1359d6195ef38
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.redox.2022.102253