Circadian Variation of Cardiac K ⁺ Channel Gene Expression

Abstract

Background— Many cardiac arrhythmias have their own characteristic circadian variations. Because the expression of many genes, including clock genes, is regulated variably during a day, circadian variations of ion channel gene expression, if any, could contribute to the fluctuating alterations of cardiac electrophysiological characteristics and subsequent arrhythmogenesis. Methods and Results— To examine whether cardiac K + channel gene expression shows a circadian rhythm, we analyzed the mRNA levels of 8 Kv and 6 Kir channels in rat hearts every 3 hours throughout 1 day. Among these channels, Kv1.5 and Kv4.2 genes showed significant circadian variations in their transcripts: ≈2-fold increase of Kv1.5 mRNA from trough at Zeitgeber time (ZT) 6 to peak at ZT18 and a completely reverse pattern in Kv4.2 mRNA (≈2-fold increase from trough at ZT18 to peak at ZT6). Actually, along with the variations in the immunoreactive proteins, the density of the transient outward and steady-state currents in isolated myocytes and the responses of atrial and ventricular refractoriness to 4-aminopyridine in isolated-perfused hearts showed differences between ZT6 and ZT18, a circadian pattern comparable to that of Kv1.5 and Kv4.2 gene expression. Reversal of light stimulation almost inverted these circadian rhythms, although pharmacological autonomic blockade only partially attenuated the rhythm of Kv1.5 but not of Kv4.2 transcripts. Conclusions— Among all the cardiac K + channels, Kv1.5 and 4.2 channels are unique in showing characteristic circadian patterns in their gene expression, with Kv1.5 increase during the dark period partially dependent on β-adrenergic activities and Kv4.2 increase during the light period independent of the autonomic nervous function.

Circadian changes of ether-a-go-go-related-gene (Erg) potassium channel transcripts in the rat pancreas and β-cell

“…Images of a Z-series were combined into a single image using the software program (Scanware, Leica). [10][11][12][13][14][15][16][17][18][19][20] were seeded onto glass coverslips (4 mm in diameter), coated with poly-L-lysine (Biochrome, Berlin, Germany) and were used after 3-5 days of incubation. The coverslip was placed into a perfusion chamber …”

“…According to Itri et al [10], potassium channels are likely candidates to couple clock-related gene expression to membrane excitability, and thus also to secretion phenomena. Kv3.1b and Kv3.2 in the hypothalamic nucleus suprachiasmaticus (SCN) [10], Kv1.5 and Kv4.2 in heart [11] and the calcium-activated potassium channel Kcnma1 in the SCN [12] reportedly vary in expression levels in a circadian manner. Finally, the ether-a-go-go-related gene channel Erg1 (Kcnh2) was listed as being circadianly expressed in heart by Storch et al [13].…”

Consequences of Circadian and Sleep Disturbances for the Cardiovascular System

“…Mechanistically, this may also be regulated intrinsically by ion channels in the heart that influence myofilament activation 156,157 some of which exhibit diurnal variation. Time-of day dependent oscillations have been reported in the heart for the voltage dependent potassium channels K v 1.5 and K v 4.2 158 , and the L-type voltage-gated calcium channel subunit VGCCα1D. 159 Also, L-type calcium channel current densities increase during the active period which is consistent with the nocturnal elevation in murine heart rate.…”

Linking the Cardiomyocyte Circadian Clock to Myocardial Metabolism

“…This study revealed that two voltage gated K + (K v ) channels, 1.5 and 4.2, exhibit marked circadian rhythms, K v 1.5 peaking during the night and 4.2 during the day (at both mRNA and protein levels). Circadian oscillations of these K + channels correlated with diurnal variations in the electrical properties of isolated papillary muscles, suggesting functional alterations [91].…”

“…Ventricular tachyarrhythmias occur with a greater incidence in the daytime compared to the night [86][87][88], while atrial fibrillation is antiphase, peaking during the night [89,90]. Yamashita et al [91] have suggested that fluctuations in arrythmias may not only be caused by autonomic stimulation, but possibly by differential expression of K + channels within cardiomyocytes, in a time of day dependent manner. This study revealed that two voltage gated K + (K v ) channels, 1.5 and 4.2, exhibit marked circadian rhythms, K v 1.5 peaking during the night and 4.2 during the day (at both mRNA and protein levels).…”