Nav1.9

Description: sodium channel, voltage-gated, type XI, alpha
Gene: Scn11a Synonyms: nav3.1, nav1.9, scn11a

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Introduction

The gene SCN11A (also known as NaN; SNS-2; NAV1.9; SCN12A) encodes Nav1.9, a voltage-gated sodium channel alpha subunit, type XI. Although Nav1.9 shares only 50% identity with most of the other Nav isoforms, it does not, based on phylogeny, belong to a new Na channel subfamily. Nav1.9 is best known for its high expression levels in peripheral sensory neurons and is thought to carry the NaN current, a persistent and tetrodrotoxin (TTX)-resistant voltage-gated Na Current , possibly involved in pain-related signaling [1438].

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Gene

The tetrodotoxin resistant NaV1.5, NaV1.8, and NaV1.9 are closely related ( see phylogenetic tree, fig. 2B in Catterall [817]), and their amino acid sequences are greater than 64% identical to those of the four sodium channels encoded on chromosome 2 (the highly tertodotoxin sensitive NaV1.1, NaV1.2, NaV1.3, and NaV1.7). [817]

RGD ID	Chromosome	Position	Species
3630	8	124724493-124794654	Rat
735313	9	119662881-119734574	Mouse
1342640	3	38887260-38992052	Human

Scn11a : sodium channel, voltage-gated, type XI, alpha

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Transcript

Acc No	Sequence	Length	Source
NM_019265	n/A	n/A	NCBI
NM_011887	n/A	n/A	NCBI
NM_014139	n/A	n/A	NCBI

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Ontology

Accession	Name	Definition	Evidence
GO:0001518	voltage-gated sodium channel complex	A sodium channel in a cell membrane whose opening is governed by the membrane potential.	IEA
GO:0016021	integral to membrane	Penetrating at least one phospholipid bilayer of a membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. When used to describe a protein, indicates that all or part of the peptide sequence is embedded in the membrane.	IEA
GO:0016020	membrane	Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins.	IEA
GO:0005886	plasma membrane	The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.	IEA
GO:0030424	axon	The long process of a neuron that conducts nerve impulses, usually away from the cell body to the terminals and varicosities, which are sites of storage and release of neurotransmitter.	IEA
GO:0044299	C-fiber	The axon of a dorsal root ganglion cell that are responsive to pain and temperature. C-fibers are small in diameter (0.2-1.5 um) and unmyelinated.	IEA

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Interaction

There are several molecules that increase Nav1.9 currents in DRG neurons:
-Inflammatory mediators (PGE2, serotonin, bradykinin, histamine, PGE3 and norepinephrine [223],[1440].
-Secreted proteins that augment neuronal survival (BDNF, GDNF)[1438][1442].

Mibefradil, a non-dihydropyridine ICaT antagonist, blocks Nav1.9. Amiloride, however, a preferential Cav3.2 channel blocker, had no effects on Nav1.9 current. [224].

NaV1.9 (as well as NaV1.5 and NaV1.8) is tetrodotoxin-resistant due to changes in amino acid sequence at a single position in domain I. In contrast to NaV1.1, NaV1.2, NaV1.3, and NaV1.7 which are are all four highly tetrodotoxin-sensitive. [817]

Tetrodotoxin

Nav1.9 is TTX resistant (selective) [1376]

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Protein

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Structure

Nav1.9 it is formed of 1765 residues and contains all the hallmarks of Na+ channels, including the inactivation tripeptide Ile-Phe-Met in L3. Nav1.9 also contains multiple predicted phosphorylation sites in the intracellular loops and N-glycosylation sites in the extracellular linkers [1439]. The alpha subunits - such as Nav1.9 - are organized in four homologous domains (I-IV), each of which contain six transmembrane alpha helices (S1-S6) and an additional pore loop located between the S5 and S6 segments (Fig. 1 in Catterall [817]). The pore loops line the outer, narrow entry to the pore, whereas the S5 and S6 segments line the inner, wider exit from the pore. The S4 segments in each domain contain positively charged amino acid residues at every third position. These residues serve as gating charges and move across the membrane to initiate channel activation in response to depolarization of the membrane. The short intracellular loop connecting homologous domains III and IV serves as the inactivation gate, folding into the channel structure and blocking the pore from the inside during sustained depolarization of the membrane. [817]. These alpha subunits, mediate voltage-dependent gating and conductance, while auxiliary beta subunits regulate the kinetic properties of the channel and facilitate membrane localization of the complex.

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Distribution

Nav1.9 immunoreactivity is present within the somata of small DRG neurons, along their peripheral projections to the nerve endings in the skin and cornea, and along their central projections (in the dorsal root) to terminals in substantia gelatinosa of the spinal cord: mainly in small diameter C fibres and medium-sized A-delta and a few large diameter A-beta fibres. (For further information see [1438], [1441],[871]). Its presence at nerve endings is consistent with its role of amplifying subthresold stimuli [870].

Surface localization of Nav1.9 appears to be related to its association with the cell adhesión molecule contactin/F3 [1439].

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Expression

(For further information see [1438], [871]) Nav1.9 is found primarily within small sensory neurons (<30 μm diameter) of dorsal root ganglia (DRG) and trigeminal ganglia, but not in neurons and glia within the CNS, or in muscle. Low levels of transcripts were detected in retina but not in cerebellum and spinal cord or in satellite and Schwann cells within DRG.

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Functional

Nav1.9 is relatively resistant to TTX, but has kinetic properties distinct from the similarly TTX-resistant Nav1.8, producing a persistent current with an activation potential of −70mV, close to the resting membrane potential, where it may set the threshold for activation [1441].

Modulation of the resting-closed states of NaV1.9 channels strongly influences nociceptor excitability and may provide a mecha ¡nism by which inflammatory mediators alter pain threshold [222].

Inflammatory mediators increase the Nav1.9 sodium current acting via a G-protein-dependent mechanism which up-regulate the persistent Nav1.9 current producing changes in membrane excitability sufficient to cause spontaneous activity, even at a membrane potential near –60 mV [1448].

As with Nav1.8, expression and/or function of Nav1.9 in sensory pathways is drastically reduced in various models of neuropathic pain (review [1438]):
• In DRG after neuropathic injury [1443]
• In a trigeminal ganglia model of neuropathic pain [1444]
Several models and human cases of radicular pain [1445]

Mouse models: Nav1.9 null [1446]

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Kinetics

Detailed electrophysiological measurements on isolated sensory neurons suggest that Nav1.9 has a novel gating mechanism in small diameter DRG neurons [224] that may drive spontaneous discharge during. In addition, it was demonstrated that inflammatory mediators can dynamically regulate putative Nav1.9 currents in wild-type DRG neurons isolated from mice [1440], [1438].

Activation:

Threshold -70 to -60 mV (rat DRG), -80mV (human) V-a = -47 to -54 mV (rat DRG) [868], [869], [870]; 2.93 ms at -60 mV, 4.1 ms at -50 mV, 3.5 ms at 20mV, and 2.5 ms at -10 mV. [870]

Inactivation:

V-h = -44 to -54 mV1,3; tau-h 843 ms at -60 mV, 460 ms at -50 mV, 43 ms at -20mV, and 16 ms at -10 mV [870]

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