Remodeling of Kv4.3 Potassium Channel Gene Expression under the Control of Sex Hormones

Abstract

Kv4.3 channels are important molecular components of transient K؉ currents (Ito currents) in brain and heart. They are involved in setting the frequency of neuronal firing and heart pacing. Altered Kv4.3 channel expression has been demonstrated under pathological conditions like heart failure indicating their critical role in heart function. Thyroid hormone studies suggest that their expression in the heart may be hormonally regulated. To explore the possibility that sex hormones control Kv4.3 expression, we investigated whether its expression changes in the pregnant uterus. This organ represents a unique model to study Ito currents, because it possesses this type of K ؉ current and undergoes dramatic changes in function and excitability during pregnancy. We cloned Kv4.3 channel from myometrium and found that its protein and transcript expression is greatly diminished during pregnancy. Experiments in ovariectomized rats demonstrate that estrogen is one mechanism responsible for the dramatic reduction in Kv4.3 expression and function prior to parturition. Furthermore, the reduction of plasma membrane Kv4.3 protein is accompanied by a perinuclear localization suggesting that cell trafficking is also controlled by sex hormones. Thus, estrogen remodels the expression of Kv4.3 in myometrium by directly diminishing its transcription and, indirectly, by altering Kv4.3 delivery to the plasma membrane.

Ionic and Cellular Basis for the Predominance of the Brugada Syndrome Phenotype in Males

“…Kv4.3 has been shown to be downregulated, resulting in reduced I to in rat myometrium at the end of pregnancy caused by a rise in estrogen levels. 30 This finding suggests the hypothesis that estrogen may regulate the expression of I to channels by diminishing the transcription of Kv4.3.…”

Female Mice Lacking Estrogen Receptor β Display Prolonged Ventricular Repolarization and Reduced Ventricular Automaticity After Myocardial Infarction

“…13,34 We showed a decreased expression of Kv4.3 (coding for I to ) in the ␤ERKO left ventricle but not in the ␣ERKO left ventricle. The expression of Kv1.5 was unchanged in both ␣ERKO and ␤ERKO animals.…”

“…We chose these channels because earlier reports suggest that the expression and function of these 2 potassium channels are likely to be dependent on the sex hormone receptor status (ie, estrogen receptors). 13,34 Whereas the transcript levels of Kv1.5 showed no significant difference, there was a significantly lower expression (PϽ0.05) of Kv4.3 in ␤ERKO mice ( Figure 5). These data are consistent with our electrophysiological data because decreased expression of Kv4.3 in female ␤ERKO mice could explain the significant prolongation of repolarization and altered ventricular automaticity in the infarcted animals with knockout of ER␤.…”

“…Furthermore, Drici et al 23 did not find gender differences with regard to QT interval, action potential duration, dispersion of refractory periods, and conduction velocities in Langendorff-perfused WT mice but described inducibility of significantly longer periods of polymorphic ventricular tachycardia in female mice uncovered by halothane, accompanied by a pronounced expression of KCNE1. Song et al 34 were the first to show a direct influence of estrogen on the transcription, ie, expression, of Kv4.3 in the myometrium of female rats. This study demonstrates, for the first time, a significant prolongation of repolarization (QT, QTc, JT, JTc) in infarcted female ␤ERKO mice but not in infarcted female ␣ERKO mice compared with noninfarcted transgenic animals and infarcted WT animals.…”

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

“…Insulin increases I to in the cardiomyocytes of diabetic rats (33,34). A-type current density in myometrial muscle cells, presumably mediated by Kv4.3, is dramatically decreased during pregnancy or after treatment with 17␤-estradiol (35). Studies of I to regulation via ␣ 1 -adrenergic, muscarinic, endothelin, and angiotensin receptors in isolated cardiomyocytes or in the Xenopus oocyte expression system reveal the important role of protein kinase C activation in I to inhibition (15, 29 -32).…”