Kv1.1 channels help set the pace

Every heartbeat is initiated in the sinoatrial node (SAN), a cluster of cells in the right atrium that rhythmically generates spontaneous action potentials that subsequently propagate to the rest of the heart. The pace of this spontaneous firing is determined, in large part, by the outward K⁺ currents that repolarize SAN myocytes after each action potential. In this issue of JGP, Si et al. report that, despite making only a relatively small contribution to these repolarizing currents, Kv1.1 channels play a significant role in regulating SAN firing frequency and the intrinsic heart rate (1).

The repolarization of SAN myocytes is mainly governed by the voltage-gated K⁺ channels Kv7.1 and Kv11.1, as well as the ATP-sensitive channel Kir6.1 (2). But many other K⁺ channels are expressed in the SAN, including multiple members of the voltage-gated Kv1 family (3, 4), and the role of these channels in cardiac pacemaking is largely unknown.

Edward Glasscock, from Southern Methodist University in Dallas, is particularly interested in Kv1.1 channels. These channels control neuronal excitability, and mutations in the gene encoding the Kv1.1 α subunit, Kcna1, are linked to epilepsy. Glasscock and colleagues have previously found that Kv1.1 also controls repolarization in the atria and ventricles of the heart (5, 6), raising the possibility that mutations in Kcna1 could cause cardiac arrhythmias that contribute to sudden unexpected death in epilepsy (SUDEP), the leading cause of epilepsy-related mortality. “We’ve been trying to figure out what Kv1.1 channels do in each region of the heart, and now we wanted to look at the SAN and the role of Kv1.1 in cardiac pacemaking,” Glasscock says.

Glasscock and colleagues, including first author Man Si, initially found that hearts isolated from Kcna1-deficient mice beat 27% slower than hearts isolated from wild-type animals (1). This was somewhat surprising because in vivo measurements show no difference in heart rate between wild-type and knockout mice. One possibility is that, in Kcna1-deficient mice, elevated autonomic tone covers up an intrinsic defect in cardiac pacemaking.

Indeed, when Si et al. analyzed the activity of isolated SAN tissue or individual SAN myocytes, they found that spontaneous firing frequency was decreased in the absence of Kcna1. Treating wild-type SAN myocytes with dendrotoxin-K, a Kv1.1-specific blocker, also reduced spontaneous firing rates.

Further analyses indicated that ablating Kv1.1 channels decreases SAN firing rates by delaying action potential repolarization. Surprisingly, however, Si et al. found that Kv1.1 channels are only present at very low levels in wild-type SAN myocytes, and the K⁺ current mediated by these channels is only a small component of the total outward currents that drive repolarization. “So, channels expressed at low levels can still have significant impacts on cardiac pacemaking,” Glasscock says.

Thus, if Kv1.1 channels play a similar role in human hearts, defects in cardiac pacemaking could potentially contribute to SUDEP in patients with mutations in KCNA1. “There are now 5 or 6 ion channel genes implicated in epilepsy that have been shown to be expressed or have functional effects in the SAN,” Glasscock explains. “So, maybe there is a class of genes expressed in the brain and pacemaker region of the heart that are high-risk factors for SUDEP.” Glasscock and colleagues now plan to distinguish the neural and cardiac effects of Kv1.1 channels using tissue-specific knockout mice.