Voltage gated sodium channels as drug discovery targets

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Abstract

Voltage-gated sodium (Na _V) channels are a family of transmembrane ion channel proteins. They function by forming a gated, water-filled pore to help establish and control cell membrane potential via control of the flow of ions between the intracellular and the extracellular environments. Blockade of Na _Vs has been successfully accomplished in the clinic to enable control of pathological firing patterns that occur in a diverse range of conditions such as chronic pain, epilepsy, and cardiac arrhythmias. First generation sodium channel modulator drugs, despite low inherent subtype selectivity, preferentially act on over-excited cells which reduces undesirable side effects in the clinic. However, the limited therapeutic indices observed with the first generation demanded a new generation of sodium channel inhibitors. The structure, function and the state of the art in sodium channel modulator drug discovery are discussed in this chapter.

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Most cited references 30

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Crystal structure of a voltage-gated sodium channel in two potentially inactivated states.

Ning Zheng, Todd Scheuer, William Catterall … (2012)

In excitable cells, voltage-gated sodium (Na(V)) channels activate to initiate action potentials and then undergo fast and slow inactivation processes that terminate their ionic conductance. Inactivation is a hallmark of Na(V) channel function and is critical for control of membrane excitability, but the structural basis for this process has remained elusive. Here we report crystallographic snapshots of the wild-type Na(V)Ab channel from Arcobacter butzleri captured in two potentially inactivated states at 3.2 Å resolution. Compared to previous structures of Na(V)Ab channels with cysteine mutations in the pore-lining S6 helices (ref. 4), the S6 helices and the intracellular activation gate have undergone significant rearrangements: one pair of S6 helices has collapsed towards the central pore axis and the other S6 pair has moved outward to produce a striking dimer-of-dimers configuration. An increase in global structural asymmetry is observed throughout our wild-type Na(V)Ab models, reshaping the ion selectivity filter at the extracellular end of the pore, the central cavity and its residues that are analogous to the mammalian drug receptor site, and the lateral pore fenestrations. The voltage-sensing domains have also shifted around the perimeter of the pore module in wild-type Na(V)Ab, compared to the mutant channel, and local structural changes identify a conserved interaction network that connects distant molecular determinants involved in Na(V) channel gating and inactivation. These potential inactivated-state structures provide new insights into Na(V) channel gating and novel avenues to drug development and therapy for a range of debilitating Na(V) channelopathies.

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Gain-of-function Nav1.8 mutations in painful neuropathy.

Catharina G Faber, Giuseppe Lauria, Ingemar Merkies … (2012)

Painful peripheral neuropathy often occurs without apparent underlying cause. Gain-of-function variants of sodium channel Na(v)1.7 have recently been found in ∼30% of cases of idiopathic painful small-fiber neuropathy. Here, we describe mutations in Na(v)1.8, another sodium channel that is specifically expressed in dorsal root ganglion (DRG) neurons and peripheral nerve axons, in patients with painful neuropathy. Seven Na(v)1.8 mutations were identified in 9 subjects within a series of 104 patients with painful predominantly small-fiber neuropathy. Three mutations met criteria for potential pathogenicity based on predictive algorithms and were assessed by voltage and current clamp. Functional profiling showed that two of these three Na(v)1.8 mutations enhance the channel's response to depolarization and produce hyperexcitability in DRG neurons. These observations suggest that mutations of Na(v)1.8 contribute to painful peripheral neuropathy.

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A de novo gain-of-function mutation in SCN11A causes loss of pain perception.

Enrico Leipold, Lutz Liebmann, G. Korenke … (2013)

The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.

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Author and article information

Journal

Journal ID (nlm-ta): Channels (Austin)

Journal ID (iso-abbrev): Channels (Austin)

Journal ID (pmc): KCHL

Title: Channels

Publisher: Taylor & Francis Group, LLC

ISSN (Print): 1933-6950

ISSN (Electronic): 1933-6969

Publication date Collection: Nov-Dec 2015

Publication date (Electronic): 8 December 2015

Publication date PMC-release: 8 December 2015

Volume: 9

Issue: 6 , Special issue on Ion Channel Pharmacology and Drug Development

Pages: 360-366

Affiliations

[1 ]Worldwide Medicinal Chemistry; Pfizer ; Great Abington, Cambridge, UK

[2 ]Worldwide Medicinal Chemistry; Pfizer ; Durham, NC USA

Author notes

[* ]Correspondence to: Sharan K Bagal; Email: sharan.bagal@ 123456pfizer.com

Article

Publisher ID: 1079674

DOI: 10.1080/19336950.2015.1079674

PMC ID: 4850042

PubMed ID: 26646477

SO-VID: 4e5c9349-0204-4517-89b7-114ec8007eb0

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License http://creativecommons.org/licenses/by-nc/3.0/, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

History

Date received : 28 July 2015

Date revision received : 29 July 2015

Date accepted : 29 July 2015

Page count

Figures: 6, Tables: 1, References: 36, Pages: 7

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