Published Online
on March 31, 2003

A more recent version of this article appeared on April 15, 2003

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Submitted on October 24, 2002
Revised on December 30, 2002
Accepted on January 7, 2003

Circadian Variation of Cardiac K⁺ Channel Gene Expression

Takeshi Yamashita MD, PhD^*, Akiko Sekiguchi PhD, Yu-ki Iwasaki MD, PhD, Kouichi Sagara MD, Hiroyuki Iinuma MD, Seiji Hatano MD, PhD, Long-Tai Fu MD, PhD, and Hiroshi Watanabe MD, PhD

From The Cardiovascular Institute, Minato-ku, Tokyo, Japan.

^* To whom correspondence should be addressed. E-mail: yamt-tky{at}umin.ac.jp.

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 -adrenergic activities and Kv4.2 increase during the light period independent of the autonomic nervous function.

Key words: circadian rhythm • ion channels • genes • electrophysiology

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