SNARE protein SNAP25 regulates the chloride-transporter KCC2 in neurons

Vineeth Andisseryparambil Raveendran; Melissa Serranilla; Azam Asgarihafshejani; Miranda de Saint-Rome; Mariia Cherednychenko; Shanelle Mullany; Jennifer A Mitchell; Jessica C Pressey; Melanie A Woodin

doi:10.1016/j.isci.2024.111156

SNARE protein SNAP25 regulates the chloride-transporter KCC2 in neurons

iScience. 2024 Oct 11;27(11):111156. doi: 10.1016/j.isci.2024.111156. eCollection 2024 Nov 15.

Authors

Vineeth Andisseryparambil Raveendran¹, Melissa Serranilla¹, Azam Asgarihafshejani¹, Miranda de Saint-Rome¹, Mariia Cherednychenko¹, Shanelle Mullany¹, Jennifer A Mitchell¹, Jessica C Pressey¹, Melanie A Woodin¹

Affiliation

¹ Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.

Abstract

Inhibitory synaptic neurotransmission mediated by GABA requires a low concentration of chloride ions (Cl^-) in neurons, which is established and maintained by the potassium-chloride co-transporter 2 (KCC2). While KCC2-interacting proteins are known to regulate KCC2 protein level and function, specific KCC2-interacting partners are still being identified and characterized. We asked whether SNAP25, an integral component of the SNARE-complex and a novel KCC2 interactor, regulates KCC2 protein and function in mice. We demonstrated that SNAP25 interacts with KCC2, and that this interaction is regulated by protein kinase C (PKC)-mediated phosphorylation. We also discovered that SNAP25 knockdown decreases total KCC2 in cortical neurons, and reduces the strength of synaptic inhibition, as demonstrated through a depolarization of the reversal potential for GABA (E_GABA), indicating reduced KCC2 function. Our biochemical and electrophysiological data combined demonstrate that SNAP25 regulates KCC2 membrane expression and function, and in doing so, regulates inhibitory synaptic transmission.

Keywords: Biological sciences; Molecular neuroscience; Neuroscience.