A Novel Regulatory Locus of Phosphorylation in the C Terminus of the Potassium Chloride Cotransporter KCC2 That Interferes with N-Ethylmaleimide or Staurosporine-mediated Activation*♦

Abstract

Background: KCC2 is a potassium-chloride cotransporter essential for hyperpolarizing neurotransmission and is associated with multiple neurological disorders.

A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

“…Weber et al also revealed that p.Thr934 and p.Ser937 phosphorylation increase KCC2 transport kinetics. 15 Therefore, the de novo variant p.Arg880Leu may also inhibit regulation of phosphorylation, which would lead to impaired KCC2 transport kinetics.…”

“…However, our finding shows that patients with EIMFS should be screened for SLC12A5 regardless of In regard to the mechanism by which SLC12A5 mutations cause EIMFS, 2 studies arrived at the same conclusion. 15 Therefore, the de novo variant p.Arg880Leu may also inhibit regulation of phosphorylation, which would lead to impaired KCC2 transport kinetics. 13 Kahle et al also reported 2 heterozygous missense variants (p.Arg952His and p.Arg1049Cys) that reside in the C-terminus and are associated with idiopathic generalized epilepsy.…”

Could tuning of the inhibitory tone involve graded changes in neuronal chloride transport?

“…A significant advantage of this method 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 over other fluorimetric (Weber et al, 2014) or radiometric assays (Rinehart et al, 2009) for assessing KCC2 function is that dynamic changes in KCC2 function in individual neurons may be evaluated and quantified. We used this procedure on untransfected hippocampal neurons and on hippocampal neurons transfected with KCC2 expression plasmids in order to compare and quantify the effect of different alanine substitutions on KCC2 transport (Fig.…”

Cation-chloride cotransporters in neuronal development, plasticity and disease

“…Dephosphorylation of threonine residues 906/1007 in the C terminus 139 is likely to be involved in the activation of KCC2 and in the consequent development of hyperpolarizing GABA A R signalling 141 (see also REF. 144). In immature hippocampal neurons, neonatal seizures trigger a fast and pronounced enhancement of KCC2-mediated Cl − extrusion, leading to ‘precocious’ hyperpolarizing GABA A R responses 11 .…”