Work

Extracellular Matrix Regulates Neuronal Chloride Concentration via K + -Cl − -Cotransporter 2

Year: 2023

Type: preprint

Abstract: The neuronal intracellular chloride concentration [Cl − ] i is critical for γ‐aminobutyric acid type A (GABA A ) receptor‐mediated transmission. Degradation of the extracellular matrix (ECM) is associated with raised [Cl − ] I but neither the mechanisms underlying this effect nor the consequences for GABA‐ mediated transmission are well understood. Hitherto it has been unclear how to reconcile the effect of the ECM on [Cl − ] i with the established role of cation‐chloride cotransporters in setting [Cl − ] I . In the present work we clarify the role of the ECM in the control of neuronal [Cl − ] i . By measuring [Cl − ] i in central neurons from male rats we show that the ECM affects basal [Cl − ] i as well as the rate of Cl − extrusion after a high load. The mechanism is not via impermeant anions but through regulation of K + ‐Cl − ‐cotransporter 2 (KCC2). ECM degradation is accompanied by an N‐type Ca 2+ ‐channel‐ and calpain‐dependent reduction in the amount of KCC2 protein, increased basal [Cl − ] i , reduced Cl − extrusion capacity as well as by reduced inhibitory, or even an excitatory, effect of intense GABA A ‐ receptor mediated trans mission. This implies a previously unrecognized pathway for the control of neuronal [Cl − ] i and excitability by the ECM. Graphical abstract

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/2023.02.09.527837