ASIC1a senses lactate uptake to regulate metabolism in neurons.

Lactate is a major metabolite largely produced by astrocytes that nourishes neurons. ASIC1a, a Na ⁺ and Ca ²⁺ -permeable channel with an extracellular proton sensing domain, is thought to be activated by lactate through chelation of divalent cations, including Ca ²⁺ , Mg ²⁺ and Zn ²⁺ , that block the channel pore. Here, by monitoring lactate-evoked H ⁺ and Ca ²⁺ 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 Ca ²⁺ 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 Ca ²⁺ 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 Ca ²⁺ response that is propagated to mitochondria to enhance lactate catabolism and suppress ROS production.
(Copyright © 2022. Published by Elsevier B.V.)