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bioRxiv · 10.1101/2023.02.09.527837

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

Yelhekar, T. D.·Kuznetsova, T.·Malinina, E.·Ponimaskin, E.·Dityatev, A.·Druzin, M.·Johansson, S.
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Abstract

The neuronal intracellular chloride concentration [Cl-]i is critical for {gamma}-aminobutyric acid type A (GABAA) 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 Ca2+-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 GABAA- receptor mediated trans mission. This implies a previously unrecognized pathway for the control of neuronal [Cl-]i and excitability by the ECM. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/527837v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1ee0d30org.highwire.dtl.DTLVardef@1a3eb1aorg.highwire.dtl.DTLVardef@a00b44org.highwire.dtl.DTLVardef@143b43f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Yelhekar, T. D., Kuznetsova, T., Malinina, E., Ponimaskin, E., Dityatev, A., Druzin, M., Johansson, S.. 2023-02-10. Extracellular Matrix Regulates Neuronal Chloride Concentration via K+-Cl--Cotransporter 2. https://doi.org/10.1101/2023.02.09.527837

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