Channelpedia

PubMed 25417810


Referenced in Channelpedia wiki pages of: none

Automatically associated channels: KCNQ1 , Kv11.1 , Kv7.1 , Kv8.2



Title: Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome.

Authors: Corey L Anderson, Catherine E Kuzmicki, Ryan R Childs, Caleb J Hintz, Brian P Delisle, Craig T January

Journal, date & volume: Nat Commun, 2014 , 5, 5535

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25417810


Abstract
It has been suggested that deficient protein trafficking to the cell membrane is the dominant mechanism associated with type 2 Long QT syndrome (LQT2) caused by Kv11.1 potassium channel missense mutations, and that for many mutations the trafficking defect can be corrected pharmacologically. However, this inference was based on expression of a small number of Kv11.1 mutations. We performed a comprehensive analysis of 167 LQT2-linked missense mutations in four Kv11.1 structural domains and found that deficient protein trafficking is the dominant mechanism for all domains except for the distal carboxy-terminus. Also, most pore mutations--in contrast to intracellular domain mutations--were found to have severe dominant-negative effects when co-expressed with wild-type subunits. Finally, pharmacological correction of the trafficking defect in homomeric mutant channels was possible for mutations within all structural domains. However, pharmacological correction is dramatically improved for pore mutants when co-expressed with wild-type subunits to form heteromeric channels.