SNAP23 regulates KCC2 membrane insertion and activity following mZnR/GPR39 activation in hippocampalneurons

Hila Asraf, Milos Bogdanovic, Noa Gottesman, Israel Sekler, Elias Aizenman, Michal Hershfinkel

Research output: Contribution to journalArticlepeer-review

Abstract

Modulation of the neuronal K+/Cl cotransporter 2 (KCC2) activity, which mediates Cl export, is critical to neuronal function. Here, we demonstrate that KCC2 interacts with the SNARE protein synaptosome-associated protein 23, SNAP23, an essential component of membrane insertion machinery. Using KCC2 truncated mutants, we show that KCC2 C-terminal domain is essential for membrane targeting and SNAP23-dependent upregulation of KCC2 activity triggered by activation of the Zn2+-sensitive receptor mZnR/GPR39 in HEK293 cells. Expression of SNAP23 phosphorylation-insensitive mutants or inhibition of its upstream activator IκB kinase (IKK) prevents mZnR/GPR39 upregulation of KCC2 activity in mouse hippocampal neurons. We further find that SNAP23 interacts with Syntaxin 1A and KCC2, and that all three proteins exhibit increased membrane insertion following mZnR/GPR39 activation in neurons. Our results elucidate a G-protein-coupled receptor-dependent pathway for regulation of KCC activity, mediated via interaction with SNARE proteins.

Original languageEnglish
Article number103751
JournaliScience
Volume25
Issue number2
DOIs
StatePublished - 18 Feb 2022

Keywords

  • Cell biology
  • Molecular physiology
  • Neuroscience

ASJC Scopus subject areas

  • General

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