Thyroid hormone receptor alpha can control action potential duration in mouse ventricular myocytes through the KCNE1 ion channel subunit.
OBJECTIVE
The reduced heart rate and prolonged QT(end) duration in mice deficient in thyroid hormone receptor (TR) alpha1 may involve aberrant expression of the K(+) channel alpha-subunit KCNQ1 and its regulatory beta-subunit KCNE1. Here we focus on KCNE1 and study whether increased KCNE1 expression can explain changes in cardiac function observed in TRalpha1-deficient mice.


METHODS
TR-deficient, KCNE1-overexpressing and their respective wildtype (wt) mice were used. mRNA and protein expression were assessed with Northern and Western blot respectively. Telemetry was used to record electrocardiogram and temperature in freely moving mice. Patch-clamp was used to measure action potentials (APs) in isolated cardiomyocytes and ion currents in Chinese hamster ovary (CHO) cells.


RESULTS
KCNE1 was four to 10-fold overexpressed in mice deficient in TRalpha1. Overexpression of KCNE1 with a heart-specific promoter in transgenic mice resulted in a cardiac phenotype similar to that in TRalpha1-deficient mice, including a lower heart rate and prolonged QT(end) time. Cardiomyocytes from KCNE1-overexpressing mice displayed increased AP duration. CHO cells transfected with expression plasmids for KCNQ1 and KCNE1 showed an outward rectifying current that was maximal at equimolar plasmids for KCNQ1-KCNE1 and decreased at higher KCNE1 levels.


CONCLUSIONS
The bradycardia and prolonged QT(end) time in hypothyroid states can be explained by altered K(+) channel function due to decreased TRalpha1-dependent repression of KCNE1 expression.
Mansén
A
A
Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
Tiselius
C
C
Sand
P
P
Fauconnier
J
J
Westerblad
H
H
Rydqvist
B
B
Vennström
B
B
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006321:Heart / Q000502:physiology*; D051657:KCNQ1 Potassium Channel / Q000502:physiology*; D051605:Kv Channel-Interacting Proteins / Q000502:physiology; D008133:Long QT Syndrome; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009206:Myocardium; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000502:physiology; D037021:Thyroid Hormone Receptors alpha / Q000502:physiology*
D051657:KCNQ1 Potassium Channel; D051605:Kv Channel-Interacting Proteins; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha