Functional and Molecular Diversity of Native Neuronal K+ Channels

Abstract

Multiple types of potassium (K+) currents have been distinguished in central and peripheral neurons based on differences in gating, time‐ and voltage‐dependent properties and pharmacological sensitivities. The various K+ currents function to control neuronal resting membrane potentials, action potential waveforms and repetitive firing properties. In addition, the cellular and sub‐cellular expression patterns of the underlying K+ channels are distinct, suggesting unique roles in regulating axonal and dendritic excitability and mediating the responses to synaptic inputs, as well as influencing short‐ and long‐term changes in neuronal functioning, plasticity and homeostasis. Molecular cloning has revealed considerable diversity of K+ channel pore‐forming (α) and of cytosolic and transmembrane accessory (β) subunits, and accumulating evidence suggests that native neuronal K+ channels, like other types of ion channels, function in macromolecular protein complexes. The individual (or combinations of) channel accessory subunits in these complexes, post‐translational modifications of channel subunits, as well as interactions with intracellular mediators and other types of voltage‐gated ion channels, influence the properties and the functioning of neuronal K+ channels. The theme of this article is the electrophysiological and molecular diversity of neuronal K+ channels and the molecular mechanisms that control the expression, distribution and functioning of native neuronal K+ channels with a focus on rapidly activating and inactivating voltage‐gated A‐type K+ channels for illustrative purposes.

Key Concepts

  • Multiple types of voltage‐dependent and voltage‐independent K+ currents have been distinguished in mammalian peripheral and central neurons based on differences in biophysical and pharmacological properties.
  • The electrophysiological diversity of neuronal K+ currents has a functional significance in that the different K+ currents contribute to determining resting membrane potentials, action potential waveforms, repetitive firing properties and responses to neurotransmitters and modulators.
  • In most mammalian neurons, multiple functionally distinct types of K+ currents/channels are co‐expressed and several are differentially distributed in neuronal cell bodies, dendrites and axons.
  • A rather large number of K+‐channel pore‐forming (α) subunits have been identified, many of which are expressed in peripheral and in central neurons, and considerable progress has been made in defining the relationships between the expressed K+‐channel α subunits and functional neuronal K+ channels.
  • A number of cytosolic and transmembrane K+‐channel auxiliary subunits have also been identified, and increasing evidence suggests that neuronal K+ channels function in macromolecular protein complexes.
  • Multiple transcriptional, post‐transcriptional, and post‐translational mechanisms contribute to native neuronal K+‐channel diversity, distribution and functioning.

Keywords: action potentials; repolarisation; repetitive firing; voltage‐gated K+ channels; non‐voltage‐gated K+ channels; Ca2+‐dependent K+ channels; K+ channel subunits; macromolecular channel protein complexes; channel regulatory mechanisms

Figure 1. Representative neuronal action potential waveform and underlying ionic currents. A prototypical evoked (by a brief depolarising current injection, Iinj) action potential and the ionic currents that contribute to shaping neuronal action potentials in diverse types of mammalian neurons are schematised. Each simulated current waveform indicates the time of the current during the action potential. The individual currents are labelled to the right of each simulated record (see also Table). Voltage‐gated inward Na+ (Nav) and Ca2+ (Cav) currents underlie the depolarising phase of the action potential, and multiple types of voltage‐gated and non‐voltage‐gated K+ currents contribute to action potential repolarisation. There are many neuronal K+ currents that contribute to setting membrane potentials and shaping action potentials (see also Table). Importantly, and as illustrated, repolarising outward K+ currents are much more numerous and diverse than the depolarising inward Na+ and Ca2+ currents, and in most neurons multiple types of K+ currents are co‐expressed. Cell‐type‐specific differences in the densities and in the detailed properties of the various repolarising K+ currents contribute to differences in the waveforms of action potentials and the repetitive firing properties of different types of peripheral and central neurons.
Figure 2. Pore‐forming subunits of neuronal K+ channels. Phylogenetic dendrogram of K+ channel pore‐forming (α) subunits of the voltage‐gated (Kv), Ca2+‐dependent (KCa), Na+‐dependent (KNa), inwardly rectifying (Kir) and two pore domain (K2P) K+ channel subfamilies. Each subfamily is shown in a different colour, with the transmembrane segments, the transmembrane topologies and the K+ selective pore regions indicated in the adjacent schematics. The voltage‐sensing fourth transmembrane domains in the six transmembrane domain spanning K+ channel α subunits are shown in yellow.
Figure 3. Native Kv4‐encoded neuronal IA channels function in macromolecular protein complexes. Cross section of a schematised neuronal IA channel complex in a membrane showing two Kv4.2 α subunits (blue), generated on the basis of the structure of Kv1.2, each interacting with a cytosolic KChIP2 (red), adapted from the structural data of Kv4.3N–KChIP1 complexes, as well as a cytosolic Kvβ (dark green) accessory subunit (in a 1 : 1 : 1 stoichiometry) through distinct, non‐overlapping Kv N‐terminal domains. The transmembrane accessory subunits DPP6/10 (brown), MinK/MiRPs (yellow), Navβ1/Navβ2 (red), as well as SEMA3A (Boczek et al., ) (bright green), each of which has also been proposed to interact with Kv4 α subunits and to contribute to the formation of native Kv4‐encoded channels, are also shown. Note that the DPP6/10, MinK/MiRPs, Navβ1/Navβ2 and SEM3A accessory subunits are each shown here in a 2 : 1 (two Kv4.2 α subunits to one of each accessory subunit) stoichiometry for illustration purposes, as the subunit stoichiometries of native channels have not been determined. Kv4‐encoded neuronal IA channels have also been suggested to interact directly through actin‐binding proteins, such as Filamin C (Petrecca et al., ), with the cytoskeleton. Two voltage‐gated Na+ (Nav) channels (orange), each comprising a pore‐forming Nav α subunit and accessory Navβ1/Navβ2 subunits, are also shown (see text).
Figure 4. Multiple mechanisms regulate neuronal K+ channel expression, distribution and properties. The expression and functioning of neuronal K+ (and other) channels (green) are regulated by transcriptional, post‐transcriptional, post‐translational and epigenetic mechanisms. Transcription factors and signaling pathways, for example, regulate the temporal and spatial patterns of K+ channel expression during nervous system development, as well as in response to neuronal activity, injury or disease. Post‐transcriptional mechanisms, such as alternative splicing and RNA editing, also impact K+‐channel expression levels, whereas post‐translational modifications, including phosphorylation, sumoylation, palmitoylation and glycosylation, contribute to the dynamic regulation of K+‐channel trafficking and functioning. Ca2+ entry through voltage‐gated Ca2+ channels (pink) and increased intracellular Ca2+ levels also affect the properties and functioning of some K+ channels directly through Ca2+‐sensing domains or Ca2+‐dependent accessory proteins, or indirectly by modulating Ca2+‐sensitive transcriptional programs and/or Ca2+‐dependent enzymes, such as protein kinases and phosphatases. Entry of Na+ through voltage‐dependent or voltage‐independent Na+ channels (orange) can also affect the functioning of neuronal Na+‐dependent K+ channels. Although less well studied, it also seems certain that epigenetic mechanisms contribute to the regulation of neuronal K+ channel gene expression.
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Further Reading

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Nerbonne, Jeanne M(May 2016) Functional and Molecular Diversity of Native Neuronal K+ Channels. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000049]