The brain-specific kinase LMTK3 regulates KCC2-dependent neuronal Cl- extrusion

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 GABA A R 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.