Emerging roles for ether‐á‐go‐go‐related gene potassium channels in the brain

Voltage-activated ether-a-go-go-related gene (ERG1a, Kv11) potassium channels play a prominent role in regulating cardiac excitability and in heart disease. Recently, ERG channels were found to be widely distributed in brain (Papa et al. 2003; Guasti et al. 2005), although little is currently known regarding their functional role in the nervous system. In this issue of The Journal of Physiology, Pessia and colleagues (Pessia et al. 2008) describe the contribution made by these channels to the spike-generating mechanisms of medial vestibular nucleus (MVN) neurones in C57/BL/6 mice. Here, we discuss these new findings in the context of the more established roles of ERG channels in the heart. ERG channel subunits are the principal components of the rapid delayed rectifier (IKr) channel in heart (Sanguinetti et al. 1995; Trudeau et al. 1995). The physiological role of IKr is to contribute to the repolarization of cardiac action potentials (Sanguinetti & Jurkiewicz, 1990). Mutations in the human ERG (HERG) channel gene are linked to prolonged repolarization and cardiac arrhythmias (Curran et al. 1995) and this finding established the critical role of HERG channels in providing for efficient cardiac repolarization. Indeed, ERG channels are optimized for repolarization of long-duration ventricular action potentials. Outward currents in ERG channels paradoxically increase (or resurge) with membrane repolarization and are timed to occur at the terminal phase of cardiac action potentials (Fig. 1). The resurgent current is regulated by unconventional biophysics of channel gating. With an initial depolarizing voltage pulse, channels slowly transition from a closed to an open state, but quickly enter an inactive, non-conducting state that limits outward current. Upon repolarization, the channels quickly recover from inactivation and re-enter an open state; however, a comparatively slow return to the closed state gives rise to a large resurgent current that helps terminate the plateau phase of the cardiac action potential. Figure 1 Unique gating properties of ether-a-go-go-related gene K+ channels Upper panel, illustrations depicting the three conductance states of ERG K+ channels (closed, open and inactivated). Lower panel, idealized macroscopic current corresponding to the conductance . Gating of cardiac IKr is also regulated by interactions between ERG isoforms. Two isoforms of ERG, including the original isolate, ERG1a, and a differently spliced isoform, ERG1b, co-associate to form native IKr channels in the mammalian heart (Jones et al. 2004). In brain, the determinants of a native conductance are anticipated to be more complex, since in addition to the alternatively spliced isoforms of ERG1, the nervous system also contains ERG2 and ERG3 channel subunits. Using polyclonal antibodies directed against each of the ERG channel proteins expressed in brain, Pessia et al. (2008) demonstrate that ERG1a, 1b, 3 and, to a lesser extent, ERG 2 are localized in neurones scattered throughout the vestibular nuclei. Labelling, which was preferentially associated with neuronal soma, did not differ appreciably between newborn and adult mice suggesting that ERG K+ channels may have a functional role in early postnatal development as well as in the adult animal. The contribution made by native ERG currents in regulating the excitability of medial vestibular neurones (MVNs) was investigated in a thoughtful series of experiments comparing the effects of the class III anti-arrhythmic agents and selective ERG channel blockers, WAY-123,398 and E4031, on spontaneous and current-evoked spiking in brain slices. Between two-thirds and three-quarters of the MVN neurones examined using extracellular and whole-cell current clamp recording techniques exhibited an increase in spontaneous activity accompanied by a reduction in the precision of firing after ERG channel block. The changes were paralleled by enhanced responsiveness to current injection that included an increase in firing frequency and the voltage trajectory between spikes as well as a reduction in latency to onset of current-evoked spiking and a decrease in spike frequency adaptation. Several interesting implications derive from these results. The observed changes in basal firing rate and discharge pattern support the proposition that ERG K+ channels are at least partially open during the autogenous pacemaking activity exhibited by these neurones in vitro. Similarly, the ability of ERG blockers to increase the trajectory of the membrane potential in the interval between spikes and to reduce first spike latency suggests that a brief membrane depolarization is sufficient to activate enough ERG current to alter the electroresponsive properties of MVN neurones. A characteristically slow rate of channel deactivation ensures that incremental activation of ERG K+ current summates to produce a ‘use-dependent’ change in neuronal excitability that contributes to spike frequency adaptation (Schonherr et al. 1999). The results of Pessia et al. (2008) extend the growing list of CNS neurones in which native ERG channels have been unambiguously shown to contribute to firing pattern and excitability. As the role of these channels in brain comes into focus, we can begin to examine the central effects of the genetic mutations and broad category of drugs known to alter ERG function in the heart with an eye toward defining the role of these channels in CNS diseases and therapeutic actions of the drugs used to treat them.