Reciprocal Regulation of KCC2 Trafficking and Synaptic Activity.

Etienne Côme,Martin Heubl,Sabine Lévi,Jean Christophe Poncer,Eric J Schwartz

doi:10.3389/fncel.2019.00048

Abstract

The main inhibitory neurotransmitter receptors in the adult central nervous system (CNS) are type A γ-aminobutyric acid receptors (GABAARs) and glycine receptors (GlyRs). Synaptic responses mediated by GlyR and GABAAR display a hyperpolarizing shift during development. This shift relies mainly on the developmental up-regulation of the K+-Cl− co-transporter KCC2 responsible for the extrusion of Cl−. In mature neurons, altered KCC2 function—mainly through increased endocytosis—leads to the re-emergence of depolarizing GABAergic and glycinergic signaling, which promotes hyperexcitability and pathological activities. Identifying signaling pathways and molecular partners that control KCC2 surface stability thus represents a key step in the development of novel therapeutic strategies. Here, we present our current knowledge on the cellular and molecular mechanisms governing the plasma membrane turnover rate of the transporter under resting conditions and in response to synaptic activity. We also discuss the notion that KCC2 lateral diffusion is one of the first parameters modulating the transporter membrane stability, allowing for rapid adaptation of Cl− transport to changes in neuronal activity.

Highlights

Excitatory and inhibitory neurotransmission depend on the electrochemical ion gradients across the plasma membrane
The NTD of KCC2a is 23 amino acids longer than the KCC2b one (Uvarov et al, 2007) and contains a putative SPAK (STE20/SPS1-related, proline alanine-rich kinase) and OSR1 kinase (Oxydative stress response 1) interaction site. Both isoforms show similar ion transport properties when expressed in human embryonic kidney (HEK) 293 cells and cultured hippocampal and cortical neurons (Uvarov et al, 2007; Markkanen et al, 2017), but have different subcellular localization in vivo and in vitro, suggesting a contribution of the NTD to the subcellular targeting of the transporter in given cells, probably via the binding to selective partners
In contrast to full KCC2 knockout mice, which die at birth due to respiratory failure (Hübner et al, 2001), KCC2b knockout mice are viable until postnatal age 15 (P15; Woo et al, 2002)

Summary

INTRODUCTION

Excitatory and inhibitory neurotransmission depend on the electrochemical ion gradients across the plasma membrane. The NTD of KCC2a is 23 amino acids longer than the KCC2b one (Uvarov et al, 2007) and contains a putative SPAK (STE20/SPS1-related, proline alanine-rich kinase) and OSR1 kinase (Oxydative stress response 1) interaction site (de Los Heros et al, 2014; Table 1) Both isoforms show similar ion transport properties when expressed in human embryonic kidney (HEK) 293 cells and cultured hippocampal and cortical neurons (Uvarov et al, 2007; Markkanen et al, 2017), but have different subcellular localization in vivo (in neurons of the deep cerebellar nucleus, the pons and the medulla) and in vitro (cultured hippocampal neurons; Markkanen et al, 2014, 2017), suggesting a contribution of the NTD to the subcellular targeting of the transporter in given cells, probably via the binding to selective partners.

Developmental Expression

Subcellular Expression

Posttranslational Regulatory Mechanisms