ClC-3 regulates the excitability of nociceptive neurons and is involved in inflammatory processes within the spinal sensory pathway

Frontiers in Cellular Neuroscience

Neuroscience

Stefanie Bungert-Plümke¹  Christoph Fahlke¹  Jana Gehlen¹  Frank Müller¹  Juan Sierra-Marquez¹  Raul E. Guzman¹  Angelika Lampert²  Antje Willuweit³  Carina Balduin³  Michael Schöneck³ 

[1] Institute of Biological Information Processing, Molecular and Cellular Physiology (IBI-1), Forschungszentrum Jülich, Jülich, Germany;Institute of Physiology, RWTH Aachen, Aachen, Germany;Medical Imaging Physics, Institute of Neuroscience and Medicine (INM-4), Forschungszentrum Jülich, Jülich, Germany;

关键词: ClC-3;    chloride-proton exchanger;    neuronal excitability;    pain;    microglia activation;    action potential;    DRG;   

DOI  :  10.3389/fncel.2022.920075

 received in 2022-04-20, accepted in 2022-07-28,  发布年份 2022

来源: Frontiers

【 摘 要 】

ClC-3 Cl–/H+ exchangers are expressed in multiple endosomal compartments and likely modify intra-endosomal pH and [Cl–] via the stoichiometrically coupled exchange of two Cl– ions and one H+. We studied pain perception in Clcn3–/– mice and found that ClC-3 not only modifies the electrical activity of peripheral nociceptors but is also involved in inflammatory processes in the spinal cord. We demonstrate that ClC-3 regulates the number of Nav and Kv ion channels in the plasma membrane of dorsal root ganglion (DRG) neurons and that these changes impair the age-dependent decline in excitability of sensory neurons. To distinguish the role of ClC-3 in Cl–/H+ exchange from its other functions in pain perception, we used mice homozygous for the E281Q ClC-3 point mutation (Clcn3E281Q/E281Q), which completely eliminates transport activity. Since ClC-3 forms heterodimers with ClC-4, we crossed these animals with Clcn4–/– to obtain mice completely lacking in ClC-3-associated endosomal chloride–proton transport. The electrical properties of Clcn3E281Q/E281Q/Clcn4–/– DRG neurons were similar to those of wild-type cells, indicating that the age-dependent adjustment of neuronal excitability is independent of ClC-3 transport activity. Both Clcn3–/– and Clcn3E281Q/E281Q/Clcn4–/– animals exhibited microglial activation in the spinal cord, demonstrating that competent ClC-3 transport is needed to maintain glial cell homeostasis. Our findings illustrate how reduced Cl–/H+ exchange contributes to inflammatory responses and demonstrate a role for ClC-3 in the homeostatic regulation of neuronal excitability beyond its function in endosomal ion balance.

【 授权许可】

Unknown   
Copyright © 2022 Sierra-Marquez, Willuweit, Schöneck, Bungert-Plümke, Gehlen, Balduin, Müller, Lampert, Fahlke and Guzman.