Channelpedia

PubMed 27228168


Referenced in Channelpedia wiki pages of: none

Automatically associated channels: KCNK , KCNK3 , KCNK5



Title: Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy.

Authors: Alan P Reed, Giovanna Bucci, Firdaus Abd-Wahab, Stephen J Tucker

Journal, date & volume: PLoS ONE, 2016 , 11, e0156456

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/27228168


Abstract
TASK-2, a member of the Two-Pore Domain (K2P) subfamily of K+ channels, is encoded by the KCNK5 gene. The channel is expressed primarily in renal epithelial tissues and a potentially deleterious missense variant in KCNK5 has recently been shown to be prevalent amongst patients predisposed to the development of Balkan Endemic Nephropathy (BEN), a chronic tubulointerstitial renal disease of unknown etiology. In this study we show that this variant (T108P) results in a complete loss of channel function and is associated with a major reduction in TASK-2 channel subunits at the cell surface. Furthermore, these mutant subunits have a suppressive or 'dominant-negative' effect on channel function when coexpressed with wild-type subunits. This missense variant is located at the extracellular surface of the M2 transmembrane helix and by using a combination of structural modelling and further functional analysis we also show that this highly-conserved threonine residue is critical for the correct function of other K2P channels. These results therefore provide further structural and functional insights into the possible pathophysiological effects of this missense variant in TASK-2.