TY - JOUR
T1 - Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia
AU - David, Jens-Peter
AU - Lisewski, Ulrike
AU - Crump, Shawn M
AU - Jepps, Thomas A
AU - Bocksteins, Elke
AU - Wilck, Nicola
AU - Lossie, Janine
AU - Roepke, Torsten K
AU - Schmitt, Nicole
AU - Abbott, Geoffrey W
PY - 2019/2
Y1 - 2019/2
N2 - KCNE5 is an X-linked gene encodingKCNE5, an ancillary subunit to voltage-gated potassium (KV) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout (Kcne52/0) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5+/0 mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte KV current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current (Ito,f). The current increases arose from an apex-specific increase in slow transient outward current-1 (IKslow,1) (conducted byKV1.5) and Ito,f (conducted byKV4)andanincrease inIKslow,2 (conducted byKV2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricularmyocytes, whereKV2.1was also detected in both Kcne52/0 and Kcne5+/0 mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and KV2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases IK,slow2 by reducingKV2.1 intracellular sequestration. The human AF-associatedmutationKCNE5-L65F negative shifted the voltage dependence of KV2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in KV2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation ofKV2.1 inmouse heart. Increased KV current is a manifestation of KCNE5 disruption that is most likely common to bothmouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.
AB - KCNE5 is an X-linked gene encodingKCNE5, an ancillary subunit to voltage-gated potassium (KV) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout (Kcne52/0) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5+/0 mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte KV current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current (Ito,f). The current increases arose from an apex-specific increase in slow transient outward current-1 (IKslow,1) (conducted byKV1.5) and Ito,f (conducted byKV4)andanincrease inIKslow,2 (conducted byKV2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricularmyocytes, whereKV2.1was also detected in both Kcne52/0 and Kcne5+/0 mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and KV2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases IK,slow2 by reducingKV2.1 intracellular sequestration. The human AF-associatedmutationKCNE5-L65F negative shifted the voltage dependence of KV2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in KV2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation ofKV2.1 inmouse heart. Increased KV current is a manifestation of KCNE5 disruption that is most likely common to bothmouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.
U2 - 10.1096/fj.201800502r
DO - 10.1096/fj.201800502r
M3 - Journal article
C2 - 30289750
SN - 0892-6638
VL - 33
SP - 2537
EP - 2552
JO - FASEB journal : official publication of the Federation of American Societies for Experimental Biology
JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology
IS - 2
ER -