Trends in Neurosciences
Volume 28, Issue 8, August 2005, Pages 422-428
Journal home page for Trends in Neurosciences

For K+ channels, Na+ is the new Ca2+

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Although K+ channels activated by Ca2+ have long been known to shape neuronal excitability, evidence is accumulating that K+ channels sensitive to intracellular Na+, termed KNa channels, have an equally significant role. KNa channels contribute to adaptation of firing rate and to slow afterhyperpolarizations that follow repetitive firing. In certain neurons, they also appear to be activated by Na+ influx accompanying a single spike. Two genes encoding these channels, Slick and Slack, are expressed throughout the brain. The spatial localization of KNa channels along axons, dendrites and somata appears to be highly cell-type specific. Their molecular properties also suggest that these channels contribute to the response of neurons to hypoxia.

Introduction

Most of the K+ channels that regulate neuronal excitability do so by sensing voltage across the plasma membrane and adjusting the flow of K+ accordingly. One important class of K+ channels, however, represents those that become activated by the accumulation of intracellular ions such as Ca2+ or Na+. One particularly interesting aspect of the activity of such channels is that, because the concentrations of these ions change much more slowly than voltage, they can integrate and respond to the recent pattern of neuronal firing.

Perhaps because elevation of intracellular Ca2+ levels has a key signaling role in nearly all known cell types, including non-neuronal cells, Ca2+-activated K+ channels have been characterized extensively. These channels are encoded by the Slo gene 1, 2, 3 or are members of the SK K+ channel family 4, 5, 6. In contrast to Ca2+, Na+ is not generally considered an intracellular messenger. Indeed, it is only in the nervous system that large changes in intracellular Na+ concentration ([Na+]i) occur as a result of normal physiological signaling. Perhaps for this reason, Na+-activated K+ channels (KNa) are particularly highly expressed in neurons 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. KNa channels are also found in cardiac cells from some species [21], in diaphragm muscle fibers [22], in developing myoblasts [23] and in Xenopus oocytes [24]. In fact, the existence of KNa currents was first reported >20 years ago in cardiomyocytes [25].

Over the past several years, many of the physiological functions and molecular identities of KNa channels have become known. One of the surprises is that such channels can act over a wide range of timescales to influence the firing patterns of neurons. For example, in some neurons significant activation of KNa occurs with a single action potential, whereas in other neurons slow KNa activation during repetitive firing leads to subsequent suppression of excitability for tens of seconds. This might reflect the dynamics of intracellular Na+ in different cells or in different parts of a neuron, or might result from the expression of different KNa channel genes, which encode channels that have different kinetic properties and differential localization at somata or dendrites. Finally, in situ hybridization and immunohistochemical studies have revealed that KNa channels are widely expressed in the nervous system and are therefore likely to have a role in the vast majority of neuronal types.

Section snippets

Neuronal activity generates large and prolonged Na+ transients

The dynamics of intracellular Na+ in neurons have been reviewed recently [26]. Na+-sensitive microelectrodes and ratiometric imaging of [Na+]i indicate that Na+ levels in resting neurons range between ∼4 mM and 15 mM. Stimulation produces increases in [Na+]i, which in certain locations can reach as high as 100 mM. The two major routes for Na+ entry during evoked activity are through voltage-dependent Na+ channels, particularly non-inactivating (persistent) Na+ channels, and through ionotropic

KNa channels produce a slow afterhyperpolarization that follows repetitive firing

Generation of a slow afterhyperpolarization (AHP) depending on Na+ influx and following repetitive neuronal firing was first described in layer 5 pyramidal neurons of the cat sensorimotor cortex 9, 30. Development of the slow AHP results from activation of a K+ conductance and is associated with slowing of firing frequency during stimulation. Subsequently, Na+-dependent slow AHPs lasting many seconds have been described in various neurons 31, 32, 33, 34, 35, 36 including trigeminal neurons,

Activation of KNa channels produces adaptation of firing rate

The accumulation of Na+ during a burst of action potentials that leads to a prolonged slow AHP also progressively increases KNa currents during the burst itself, leading to adaptation of firing rate during the burst. It has been proposed that activation of KNa in neurons of the visual cortex leads to adaptation of firing rate in response to high-contrast visual stimuli [32]. Such adaptation occurs over several seconds of evoked firing, and is associated with a Na+-dependent slow AHP that can

KNa channels shape intrinsic bursting

Some neocortical pyramidal neurons have intrinsic electrical properties that enable them to generate repeated spontaneous bursts of action potentials that contribute to the synchronization of cortical activity. It has been shown that the amplitude and duration of the slow AHPs that separate the individual bursts in these neurons are due to activation of KNa currents [34]. These slow AHPs differ from those that regulate the interval between spindle bursts in that they are shorter, typically with

Activation of KNa following a single action potential

Characterization of rapidly activating KNa currents has been hampered by the fact that, in voltage-clamp experiments, a poorly clamped action potential produces an artifact that can be mistaken for a transient outward current blocked by tetrodotoxin and by low external Na+ levels 10, 19. Nevertheless, several recent current-clamp studies, which are not subject to such artifacts, have provided evidence that a single spike can activate KNa channels. As already described, the Na+-dependent slow

Slack encodes a slowly activating KNa channel

The K+ channel subunit known as Slack [40] (‘sequence like a Ca2+-activated K+ channel’; also termed Slo2.2) has recently been shown to be gated by Na+41, 42. Slack is the largest K+ channel subunit currently known and its sequence has limited regions of similarity to Slo, the large-conductance Ca2+-activated channel (BK channel). Like Slo, Slack has a large C-terminal region containing two ‘regulator of K+ conductance’ (RCK) domains [43] that are likely to be sites for Na+ binding and channel

Slick channels are rapidly activating KNa channels regulated by ATP

A second KNa channel gene called Slick (also termed Slo2.1), which is homologous to Slack, has also been identified [42]. Overall, the Slick protein is slightly smaller than Slack, its N-terminal being half the size of that in Slack (Figure 2). The transmembrane domains and the RCK domains of Slick and Slack are almost identical and their overall homology is ∼74%. Like Slack, Slick contains a highly conserved PDZ-binding domain that could localize the channel to specific subcellular locations.

Localization of Slack and Slick channels in the brain

Both in situ hybridization and immunocytochemical experiments indicate that Slack is widely expressed in the nervous system 40, 44 (Table 1). An antibody directed against the N-terminus of the originally cloned Slack channel shows high protein levels in the olfactory bulb, midbrain and brainstem [44]. Limited immunoreactivity was, however, found in certain regions of the neocortex, cerebellum and hippocampus, which contrasts with in situ hybridization data. The recent cloning of an alternative

Role of Slick in neuronal adaptation

Computer simulations have been carried out to address the potential contribution of Slick currents to the firing properties of neurons [46]. These simulations indicate that such currents can account for many of the phenomena attributed to KNa currents in neurons, including the adaptation of firing during maintained stimulation. In such simulations, the rapid activation of Slick can contribute to the refractory period following a single action potential. Because Slick and Slack are present at

Activation of KNa channels by ionotropic receptors

Although studies of the role of KNa channels in neurons have focused on their activation by Na+ influx through voltage-dependent channels, large elevations of [Na+]i also occur upon activation of glutamate receptors. The Slack channel has been shown to bind directly to the PDZ domain of postsynaptic density 95 (PSD-95), a major component of glutamatergic postsynaptic densities [50]. Moreover, the same study showed by immunocytochemistry that Slack colocalizes with PSD-95 in cultured mouse

Potential role for KNa channels in neuronal pathologies

In addition to regulating the firing patterns of neurons, it has been proposed that, in small dorsal root ganglion neurons, the primary function of KNa channels is to set or stabilize the resting potential [19]. The influence of KNa channels on the resting potential can become particularly significant in hypoxia, during which failure of the Na+/K+-ATPase leads to elevated [Na]i. Support for a protective role for KNa channels also comes from the finding that impairment of mitochondrial function

Concluding remarks

Changes in the behavior of an animal are frequently associated with changes in the intrinsic electrical properties of neurons. Because KNa channels have been suggested to control resting potential, adaptation, AHPs and bursting with different time courses, modulation of these channels could provide a powerful mechanism for the control of neuronal excitability. Nevertheless, although Na+ has long been known to have a specific signaling role that is absent in non-excitable cells, there remain

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