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The brain-specific kinase LMTK3 regulates neuronal excitability by decreasing KCC2-dependent neuronal Cl^{−} extrusion

Cho, N; Kontou, G; Smalley, JL; Bope, C; Dengler, J; Montrose, K; Deeb, TZ; ... Moss, SJ; + view all (2024) The brain-specific kinase LMTK3 regulates neuronal excitability by decreasing KCC2-dependent neuronal Cl^{−} extrusion. iScience , 27 (4) , Article 109512. 10.1016/j.isci.2024.109512. Green open access

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Abstract

LMTK3 is a brain-specific transmembrane serine/threonine protein kinase that acts as a scaffold for protein phosphatase-1 (PP1). Although LMKT3 has been identified as a risk factor for autism and epilepsy, its physiological significance is unknown. Here, we demonstrate that LMTK3 copurifies and binds to KCC2, a neuron-specific K+/Cl− transporter. KCC2 activity is essential for Cl−-mediated hyperpolarizing GABAAR receptor currents, the unitary events that underpin fast synaptic inhibition. LMTK3 acts to promote the association of KCC2 with PP1 to promote the dephosphorylation of S940 within its C-terminal cytoplasmic domain, a process the diminishes KCC2 activity. Accordingly, acute inhibition of LMTK3 increases KCC2 activity dependent upon S940 and increases neuronal Cl− extrusion. Consistent with this, LMTK3 inhibition reduced intrinsic neuronal excitability and the severity of seizure-like events in vitro. Thus, LMTK3 may have profound effects on neuronal excitability as an endogenous modulator of KCC2 activity.

Type: Article
Title: The brain-specific kinase LMTK3 regulates neuronal excitability by decreasing KCC2-dependent neuronal Cl^{−} extrusion
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.isci.2024.109512
Publisher version: http://dx.doi.org/10.1016/j.isci.2024.109512
Language: English
Additional information: © 2024 Published by Elsevier Inc. under a Creative Commons license (http://creativecommons.org/licenses/by-nc/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10190940
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