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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Biol+Chem
2016 ; 291
(39
): 20387-401
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The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an
Unusual Target for Protease-mediated Damage
#MMPMID27502273
Lamothe SM
; Guo J
; Li W
; Yang T
; Zhang S
J Biol Chem
2016[Sep]; 291
(39
): 20387-401
PMID27502273
show ga
The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of
the rapidly activating delayed rectifier potassium channel (IKr), which is
important for cardiac repolarization. Dysfunction of hERG causes long QT syndrome
and sudden death, which occur in patients with cardiac ischemia. Cardiac ischemia
is also associated with activation, up-regulation, and secretion of various
proteolytic enzymes. Here, using whole-cell patch clamp and Western blotting
analysis, we demonstrate that the hERG/IKr channel was selectively cleaved by the
serine protease, proteinase K (PK). Using molecular biology techniques including
making a chimeric channel between protease-sensitive hERG and insensitive human
ether-a-go-go (hEAG), as well as application of the scorpion toxin BeKm-1, we
identified that the S5-pore linker of hERG is the target domain for proteinase K
cleavage. To investigate the physiological relevance of the unique susceptibility
of hERG to proteases, we show that cardiac ischemia in a rabbit model was
associated with a reduction in mature ERG expression and an increase in the
expression of several proteases, including calpain. Using cell biology
approaches, we found that calpain-1 was actively released into the extracellular
milieu and cleaved hERG at the S5-pore linker. Using protease cleavage-predicting
software and site-directed mutagenesis, we identified that calpain-1 cleaves hERG
at position Gly-603 in the S5-pore linker of hERG. Clarification of
protease-mediated damage of hERG extends our understanding of hERG regulation.
Damage of hERG mediated by proteases such as calpain may contribute to
ischemia-associated QT prolongation and sudden cardiac death.
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