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Peer-reviewedCC BYEMBO Reports

Differential isoform-specific control of KCC2 function in developing and mature cortical neurons

  • Carla Pagan1
  • Pauline Weinzettl1
  • Marika A Markkanen2
  • Marion Russeau1
  • Matti S Airaksinen2
  • Jean-Christophe Poncer1
  1. 1Institut du Fer à Moulin, Inserm, Sorbonne Université
  2. 2Department of Anatomy, Faculty of Medicine, University of Helsinki
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Abstract

The K-Cl cotransporter KCC2 is essential for fast synaptic inhibition in the mature brain. It is encoded by a single gene and expressed as two isoforms: KCC2a and KCC2b, which differ in their N-terminal domains. While KCC2b is predominant, the function of the weakly expressed KCC2a isoform remains unclear. Here, we reveal that KCC2a is a potent, bidirectional regulator of KCC2b membrane stability and function in cortical neurons. In immature neurons, where WNK-SPAK kinase activity is high, KCC2a promotes SPAK-dependent phosphorylation of KCC2b at Thr1007, which likely contributes to hindering its membrane expression and function. Conversely, in mature neurons with low basal WNK-SPAK activity, KCC2a promotes KCC2b expression, clustering, and function. At this stage, although accounting for less than 5% of total KCC2 mRNA, KCC2a is enriched in dendrites and within KCC2 clusters, where it prevents clathrin-mediated KCC2b endocytosis, as well as polyubiquitination and proteasomal degradation. Thus, KCC2a acts as a developmental switch that first inhibits KCC2b during early development and then ensures its membrane stability to support effective synaptic inhibition in the adult brain.

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Cite

BibTeXRIS
BibTeX
@article{pagan2026differential,
  title = {{Differential isoform-specific control of KCC2 function in developing and mature cortical neurons}},
  author = {Carla Pagan and Pauline Weinzettl and Marika A Markkanen and Marion Russeau and Matti S Airaksinen and Jean-Christophe Poncer},
  journal = {EMBO Reports},
  year = {2026},
  month = sep,
  doi = {10.1038/s44319-026-00920-3},
  url = {https://doi.org/10.1038/s44319-026-00920-3},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Differential isoform-specific control of KCC2 function in developing and mature cortical neurons
AU  - Carla Pagan
AU  - Pauline Weinzettl
AU  - Marika A Markkanen
AU  - Marion Russeau
AU  - Matti S Airaksinen
AU  - Jean-Christophe Poncer
PY  - 2026
DA  - 2026/09/01
JO  - EMBO Reports
DO  - 10.1038/s44319-026-00920-3
UR  - https://doi.org/10.1038/s44319-026-00920-3
AB  - The K-Cl cotransporter KCC2 is essential for fast synaptic inhibition in the mature brain. It is encoded by a single gene and expressed as two isoforms: KCC2a and KCC2b, which differ in their N-terminal domains. While KCC2b is predominant, the function of the weakly expressed KCC2a isoform remains unclear. Here, we reveal that KCC2a is a potent, bidirectional regulator of KCC2b membrane stability and function in cortical neurons. In immature neurons, where WNK-SPAK kinase activity is high, KCC2a promotes SPAK-dependent phosphorylation of KCC2b at Thr1007, which likely contributes to hindering its membrane expression and function. Conversely, in mature neurons with low basal WNK-SPAK activity, KCC2a promotes KCC2b expression, clustering, and function. At this stage, although accounting for less than 5% of total KCC2 mRNA, KCC2a is enriched in dendrites and within KCC2 clusters, where it prevents clathrin-mediated KCC2b endocytosis, as well as polyubiquitination and proteasomal degradation. Thus, KCC2a acts as a developmental switch that first inhibits KCC2b during early development and then ensures its membrane stability to support effective synaptic inhibition in the adult brain.
SN  - 1469-3178
ER  -