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Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

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Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability cells Review Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability Agnes Zybura 1,2, Andy Hudmon 3 and Theodore R. Cummins 1,2,* 1 Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; [email protected] 2 Biology Department, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA 3 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; [email protected] * Correspondence: [email protected] Abstract: Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Nav1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav Citation: Zybura, A.; Hudmon, A.; isoforms, others are isoform-specific. Additionally, considerable progress has been made toward Cummins, T.R. Distinctive Properties and Powerful Neuromodulation of understanding how individual protein interactions and/or modifications affect Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Nav1.6 Sodium Channels Regulates Neuronal Excitability. Cells 2021, 10, Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this 1595. https://doi.org/10.3390/ channel’s complex regulatory mechanisms and how they may contribute to neuromodulation. cells10071595 Keywords: voltage-gated sodium channel; action potential; axon initial segment; sodium currents; Academic Editor: Alexander channelopathies; post-translational modifications; protein-protein interactions G. Obukhov Received: 3 June 2021 Accepted: 21 June 2021 1. Introduction Published: 25 June 2021 A well-functioning and healthy brain is dependent on the ability of neurons to inte- grate and relay impulses. These impulses are mediated by the activity of voltage-gated Publisher’s Note: MDPI stays neutral sodium channels (Navs) by controlling the initiation and propagation of electrical signals, with regard to jurisdictional claims in which are fine-tuned by myriad signaling events to contribute as critical regulators of published maps and institutional affil- iations. neuronal excitability [1]. Navs exist as large complex heteromultimeric structures consisting of a pore-forming α subunit that may be covalently or non-covalently bound to auxiliary subunits, chief among these being β subunits (β1–4) (Figure1)[ 2–4]. The Nav α subunit is comprised of a ~2000-amino acid polypeptide chain folded into a complex tertiary structure organized Copyright: © 2021 by the authors. into four homologous transmembrane domains (DI-DIV), each containing six α-helical Licensee MDPI, Basel, Switzerland. segments (S1–S6). The S1–S4 segments comprise the voltage sensing domain (VSD) which This article is an open access article contains a number of positively charged lysine and arginine residues along the S4 helix distributed under the terms and conditions of the Creative Commons that permit the channel to sense voltage changes across the membrane and is responsible Attribution (CC BY) license (https:// for channel activation [5]. In proximity to the VSD are the S5–S6 segments that form the creativecommons.org/licenses/by/ re-entrant P-loop and constitutes the ion-selective pore of the channel [6]. Linking the 4.0/). Cells 2021, 10, 1595. https://doi.org/10.3390/cells10071595 https://www.mdpi.com/journal/cells CellsCells2021 2021, 10, 10, 1595, x 22 of 2323 fourdomains domains of Nav of Navα subunitsα subunits are multiple are multiple intracellular intracellular loops loops (L1–L3) (L1–L3) in addition in addition to cyto- to cytoplasmicplasmic N- and N- and C-termini. C-termini. FigureFigure 1.1.Linear Linear schematicschematic ofof aa voltage-gatedvoltage-gated sodiumsodium channelchannelα αsubunit subunitand and an an auxiliary auxiliaryβ βsubunit. subu- L3nit. depicts L3 depicts the IFM the IFM motif motif (black (black circle) circle) for channel for channel fast inactivation.fast inactivation. InIn general, general, the the activation activation cycle cycle for for Navs Navs features features transitions transitions between between resting, resting, activated, acti- andvated, inactivated and inactivated states (Figurestates (Figure2). Under 2). Under resting resting (hyperpolarized) (hyperpolarized) conditions, conditions, Navs Navs are inare their in their closed closed state state and uponand upon depolarization depolarization transition transition into aninto open, an open, activated activated state state that allowsthat allows for sodium for sodium ion conductance,ion conductance, thus thus initiating initiating depolarization, depolarization, and and corresponds corresponds to theto the upstroke upstroke of of the the action action potential. potential. Subs Subsequently,equently, the the channel channel again again transitions transitions into into an aninactive inactive state, state, thus thus allowing allowing potassium potassium and ot andher other conductances conductances to contribute to contribute to the down- to the downstrokestroke of the of action the action potential. potential. The third The thirdintracellular intracellular loop, loop, L3, contains L3, contains an inactivation an inactivation par- particleticle consisting consisting of hydrophobic of hydrophobic residues residues (isoleucine-phenylalanine-methionine, (isoleucine-phenylalanine-methionine, IFM IFMmo- motif)tif) that that is largely is largely responsible responsible for forchannel channel fast fast inactivation inactivation [7–10]. [7–10 Notably,]. Notably, Navs Navs can canun- undergodergo various various post-translational post-translational modifications modifications (PTMs) (PTMs) and and binding interactionsinteractions withwith otherother regulatoryregulatory proteinsproteins thatthat impactimpact theirtheir structure,structure,function, function,and and traffickingtrafficking [ 11[11–13].–13]. To date, there are nine described voltage-gated sodium channel α subunit isoforms To date, there are nine described voltage-gated sodium channel α subunit isoforms (Nav1.1–Nav1.9) with distinct functional and pharmacological characteristics and expres- (Nav1.1–Nav1.9) with distinct functional and pharmacological characteristics and expres- sion patterns [14]. Sequence alignments demonstrate that the sequence homology of sion patterns [14]. Sequence alignments demonstrate that the sequence homology of mam- mammalian Nav α subunits is quite high, sharing more than 50% homology in transmem- malian Nav α subunits is quite high, sharing more than 50% homology in transmembrane brane and extracellular domains [15]. However, Navs display greater divergence within and extracellular domains [15]. However, Navs display greater divergence within intra- intracellular domains. Notably, the first intracellular loop (L1) varies in length between Nav cellular domains. Notably, the first intracellular loop (L1) varies in length between Nav isoforms and is often the target of extensive PTMs, including phosphorylation. The intra- isoforms and is often the target of extensive PTMs, including phosphorylation. The intra- cellularly accessible regions also contain additional targets for isoform-specific regulation cellularly accessible regions also contain additional targets for isoform-specific regulation by other PTMs and protein-protein interactions [11,16–19]. by other PTMs and protein-protein interactions [11,16–19]. Cells 2021, 10, x 3 of 23 Cells 2021, 10, 1595 3 of 23 Figure 2. Simplified state transition model of voltage-gated sodium channels featuring closed, open, and inactivated states. This figure was created with BioRender.com. Figure 2. Simplified state transition model of voltage-gated sodium channels featuring closed, open, Inand the inactivated 40 years states. since This Navs figu werere was first created isolated, with considerable BioRender.com. progress has been made toward mapping the vast regulatory landscape of these ion channels. However there remainsIn the much 40 years we still since do Navs not understand were first aboutisolated, Nav considerable regulation andprogress its impact has been on cellular made towardexcitability, mapping human the physiology, vast regulatory and disease. landscap In thee of brain,these theion voltage-gatedchannels. However sodium there channel re- mainsNav1.6 much is a critical we still driver do not in theunderstand initiation about and propagation Nav regulation of action and its potentials impact on in neurons.cellular excitability,Consequently, human aberrant physiology, alterations and to disease. Nav1.6 In activity the brain, can the have voltage-gated
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