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Evidence for K‐Cl cotransporter heterodimerization
Author(s) -
Ponce-Coria Jose,
Ding Jinlong,
Delpire Eric
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.694.3
Subject(s) - cotransporter , xenopus , mutation , biology , phenotype , mutant , missense mutation , wild type , genetics , microbiology and biotechnology , gene , endocrinology , chemistry , sodium , organic chemistry
In humans, mutations in the gene SLC12A6 which encodes for KCC3 result in an autosomal recessive disease, known as ACCPN (Agenesis of the Corpus Callosum associated with Peripheral Neuropathy). In the present work we focused our efforts in understanding the lethality demonstrated by the homozygosity of the Glu289Gly (E289G) mutation in the mouse K‐Cl cotransporter KCC3. This embryonic lethality, which is a much stronger phenotype than the one observed in the KCC3 knockout mouse, seem to indicate dominant negative effects of the mutant cotransporter upon other K‐Cl cotransporters. Using Xenopus laevis oocytes, as a heterologous expression system, we show that KCC2 activity and cell surface expression are significantly reduced when co‐expressing wild‐type or mutant KCC3 proteins. Interestingly, KCC2 activity was not compromised when co‐expressing KCC3 mutations (R207C and T813X) that lead to ACCPN. We also present evidence indicating that the E289G mutation impairs KCC3 glycosylation. Finally, we show that a similar mutation in KCC2 (E201G), also results in the loss of K‐Cl cotransport function through trafficking impairment to the plasma membrane.