Contactin Associates with Sodium Channel Na<sub>v</sub>1.3 in Native Tissues and Increases Channel Density at the Cell Surface

Shah, Bhaval S.; Rush, Anthony M.; Liu, Shujun; Tyrrell, Lynda; Black, Joel A.; Dib‐Hajj, Sulayman D.; Waxman, Stephen G.

doi:10.1523/jneurosci.0322-04.2004

Cited by 52 publications

(45 citation statements)

References 59 publications

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“…Common to both EphB receptors and SALMs are fibronectin type III motifs in their extracellular domains, which may be candidates for interaction with the NR1 subunit. Voltage-gated sodium channels interact directly with members of the Ig superfamily of cell adhesion molecules, including neurofascin, neuron-glia-related cell adhesion molecule, and contactin (Ratcliffe et al, 2001;McEwen and Isom, 2004;Shah et al, 2004), through an Ig loop in the extracellular domain of the ␤ subunit. This interaction is important for regulating the cell surface expression of the channel.…”

Section: Discussionmentioning

confidence: 99%

A Novel Family of Adhesion-Like Molecules That Interacts with the NMDA Receptor

Wang

Chang²,

Petralia³

et al. 2006

J. Neurosci.

118

182

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Section: Discussionmentioning

confidence: 99%

A Novel Family of Adhesion-Like Molecules That Interacts with the NMDA Receptor

Wang

Chang²,

Petralia³

et al. 2006

J. Neurosci.

118

182

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“…Contactin, which associates with VGSC ␣ subunits via ␤1, is upregulated in axotomized neurons and accumulates together with Na v 1.3 at injured axon tips in the neuroma (Shah et al, 2004). ␤2 and contactin may share a similar mechanism for increasing hyperexcitability in neuropathic pain (Isom et al, 1995;Kazarinova-Noyes et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of the Voltage-Gated Sodium Channel β2 Subunit in Neuropathic Pain Models: Characterization of Expression in Injured and Non-Injured Primary Sensory Neurons

Pertin¹,

Ji²,

Berta³

et al. 2005

J. Neurosci.

114

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The development of abnormal primary sensory neuron excitability and neuropathic pain symptoms after peripheral nerve injury is associated with altered expression of voltage-gated sodium channels (VGSCs) and a modification of sodium currents. To investigate whether the ␤2 subunit of VGSCs participates in the generation of neuropathic pain, we used the spared nerve injury (SNI) model in rats to examine ␤2 subunit expression in selectively injured (tibial and common peroneal nerves) and uninjured (sural nerve) afferents. Three days after SNI, immunohistochemistry and Western blot analysis reveal an increase in the ␤2 subunit in both the cell body and peripheral axons of injured neurons. The increase persists for Ͼ4 weeks, although ␤2 subunit mRNA measured by real-time reverse transcription-PCR and in situ hybridization remains unchanged. Although injured neurons show the most marked upregulation, ␤2 subunit expression is also increased in neighboring non-injured neurons and a similar pattern of changes appears in the spinal nerve ligation model of neuropathic pain. That increased ␤2 subunit expression in sensory neurons after nerve injury is functionally significant, as demonstrated by our finding that the development of mechanical allodynia-like behavior in the SNI model is attenuated in ␤2 subunit null mutant mice. Through its role in regulating the density of mature VGSC complexes in the plasma membrane and modulating channel gating, the ␤2 subunit may play a key role in the development of ectopic activity in injured and non-injured sensory afferents and, thereby, neuropathic pain.

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“…The subcellular distribution of Na v 1.8 and Na v 1.9 labeling in small neurons was analyzed using a method similar to those described previously (15)(16)(17). Briefly, for each image and using ImageJ software, two straight lines were drawn across well defined cells, avoiding the nucleus.…”

Section: Methodsmentioning

confidence: 99%

Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo

Lopez-Santiago

Brackenbury²,

Chen

et al. 2011

Journal of Biological Chemistry

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Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na ؉ current (I Na ) mediated by voltage-gated Na ؉ channels (VGSCs). In nociceptive DRG neurons, VGSC ␤2 subunits, encoded by Scn2b, selectively regulate TTX-S ␣ subunit mRNA and protein expression, ultimately resulting in changes in pain sensitivity. We hypothesized that VGSCs in nociceptive DRG neurons may also be regulated by ␤1 subunits, encoded by Scn1b. Scn1b null mice are models of Dravet Syndrome, a severe pediatric encephalopathy. Many physiological effects of Scn1b deletion on CNS neurons have been described. In contrast, little is known about the role of Scn1b in peripheral neurons in vivo. Here we demonstrate that Scn1b null DRG neurons exhibit a depolarizing shift in the voltage dependence of TTX-S I Na inactivation, reduced persistent TTX-R I Na , a prolonged rate of recovery of TTX-R I Na from inactivation, and reduced cell surface expression of Na v 1.9 compared with their WT littermates. Investigation of action potential firing shows that Scn1b null DRG neurons are hyperexcitable compared with WT. Consistent with this, transient outward K ؉ current (I to ) is significantly reduced in null DRG neurons. We conclude that Scn1b regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both I Na and I K .VGSCs 3 comprise one pore-forming ␣ subunit and two ␤ subunits (␤1-␤4, encoded by Scn1b-Scn4b) that do not form the pore but play critical roles in channel subcellular localization, regulation of I Na , VGSC gene transcription, and cell adhesive interactions leading to cytoskeletal modulation, changes in cell morphology, and cellular migration (1-3).All four mammalian VGSC ␤ subunit gene products are expressed in DRG neurons (4); however, little is known about their roles in nociception. The role of Scn1b in DRG neurons in vivo has not been investigated. Scn1b mRNA is expressed in DRG neurons (4), and the Scn1b splice variant ␤1B is expressed in adult rat DRG neurons as assessed by immunohistochemistry (5). Scn1b mRNA expression changes in the dorsal horn of the spinal cord in a model of neuropathic pain in rats (6), suggesting that ␤1/␤1B are important in nociception. Despite this, the effects of ␤1 on the functioning of heterologously overexpressed sensory neuronal VGSCs are controversial.

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Contactin Associates with Sodium Channel Na_v1.3 in Native Tissues and Increases Channel Density at the Cell Surface

Cited by 52 publications

References 59 publications

A Novel Family of Adhesion-Like Molecules That Interacts with the NMDA Receptor

A Novel Family of Adhesion-Like Molecules That Interacts with the NMDA Receptor

Upregulation of the Voltage-Gated Sodium Channel β2 Subunit in Neuropathic Pain Models: Characterization of Expression in Injured and Non-Injured Primary Sensory Neurons

Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo

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Contactin Associates with Sodium Channel Nav1.3 in Native Tissues and Increases Channel Density at the Cell Surface

Cited by 52 publications

References 59 publications

A Novel Family of Adhesion-Like Molecules That Interacts with the NMDA Receptor

A Novel Family of Adhesion-Like Molecules That Interacts with the NMDA Receptor

Upregulation of the Voltage-Gated Sodium Channel β2 Subunit in Neuropathic Pain Models: Characterization of Expression in Injured and Non-Injured Primary Sensory Neurons

Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo

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Contactin Associates with Sodium Channel Na_v1.3 in Native Tissues and Increases Channel Density at the Cell Surface