Functional properties and differential neuromodulation of Nav1.6 channels

Chen, Yuan; Yu, Frank H.; Sharp, Elizabeth M.; Beacham, Daniel W.; Scheuer, Todd; Catterall, William A.

doi:10.1016/j.mcn.2008.05.009

Cited by 116 publications

(125 citation statements)

References 86 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…The persistent component, measured at the end of a 50-ms pulse to -10 mV, was also significantly larger for Nav1.7r-I1461T chan- Table 1 Biophysical properties of wild-type and mutant sodium channels -61.8 ± 1.3 E (n = 37) 1.07 ± 0.07 E (n = 35) 1.04 ± 0.25 E (n = 13) 2.0 ± 0.1 E (n = 20 of 30) Nav1. 5 -88.1 ± 1.7 (n = 20) 0.9 ± 0.07 (n = 20) 0.2 ± 0.08 (n = 15) 0.6 ± 0.1 (n = 9 of 18) Nav1.5-F1486L -80.1 ± 1.6 (n = 18) 1.31 ± 0.14 E (n = 15) 0.64 ± 0.15 E (n = 10) 2.0 ± 0.4 E (n = 8 of 17) Nav1.4r -77.3 ± 2.1 (n = 11) 0.34 ± 0.03 (n = 11) 0.17 ± 0.13 (n = 10) None detected (n = 0 of 11) Nav1.4r-R1448P -91.1 ± 2.4 E (n = 20) 3.92 ± 0.25 E (n = 21) 0.95 ± 0.28 E (n = 20) 4.2 ± 0.6 E (n = 13 of 20) Nav1.6r -71.3 ± 1.9 (n = 17) 1.02 ± 0.1 (n = 17) 0.69 ± 0.16 (n = 11) 2.4 ± 0.3 (n = 8 of 14) Nav1.6r-I1477T -58.6 ± 1.2 E (n = 18) 1.25 ± 0.09 (n = 18) 7.4 ± 0.68 E (n = 14) 15.3 ± 3.4 E (n = 7 of 14)…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

et al. 2010

View full text Add to dashboard Cite

Inherited mutations in voltage-gated sodium channels (VGSCs; or Nav) cause many disorders of excitability, including epilepsy, chronic pain, myotonia, and cardiac arrhythmias. Understanding the functional consequences of the disease-causing mutations is likely to provide invaluable insight into the roles that VGSCs play in normal and abnormal excitability. Here, we sought to test the hypothesis that disease-causing mutations lead to increased resurgent currents, unusual sodium currents that have not previously been implicated in disorders of excitability. We demonstrated that a paroxysmal extreme pain disorder (PEPD) mutation in the human peripheral neuronal sodium channel Nav1.7, a paramyotonia congenita (PMC) mutation in the human skeletal muscle sodium channel Nav1.4, and a long-QT3/SIDS mutation in the human cardiac sodium channel Nav1.5 all substantially increased the amplitude of resurgent sodium currents in an optimized adult rat-derived dorsal root ganglion neuronal expression system. Computer simulations indicated that resurgent currents associated with the Nav1.7 mutation could induce high-frequency action potential firing in nociceptive neurons and that resurgent currents associated with the Nav1.5 mutation could broaden the action potential in cardiac myocytes. These effects are consistent with the pathophysiology associated with the respective channelopathies. Our results indicate that resurgent currents are associated with multiple channelopathies and are likely to be important contributors to neuronal and muscle disorders of excitability.

show abstract

Section: Resultsmentioning

confidence: 99%

“…A prime example of this phenomenon is VGSC resurgent currents. Although resurgent VGSC currents have been recorded from neurons, it has not been possible to record resurgent currents in nonexcitable heterologous expression systems (3)(4)(5), and it is not known whether VGSC mutations that cause channelopathies alter resurgent currents.…”

Section: Introductionmentioning

confidence: 99%

Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

et al. 2010

View full text Add to dashboard Cite

show abstract

“…The mammalian genome contains four voltage-gated sodium channel (VGSC) 4 ␣-subunit genes that are highly expressed in the central nervous system (CNS), SCN1A, SCN2A, SCN3A, and SCN8A, which encode the transmembrane proteins Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.6, respectively. VGSCs play a critical role in the initiation and propagation of transient depolarizing currents and electrical signaling between cells.…”

mentioning

confidence: 99%

“…Na v 1.6, the most abundantly expressed VGSC in the CNS, is localized in somata and dendrites of projection neurons, nodes of Ranvier of both peripheral and CNS neurons, and axonal initial segments (1)(2)(3). Na v 1.6 channels are expressed in a wide variety of cells, including Purkinje cells, motor neurons in the brain stem and spinal cord, pyramidal and granule neurons in the hippocampus and cortex, and glial cells and Schwann cells (4). Na v 1.6 channels are responsible for a large portion of the persistent sodium current and display several unique biophysical properties that contribute to a propensity for sustained repetitive firing (4).…”

mentioning

confidence: 99%

Dysfunction of the Scn8a Voltage-gated Sodium Channel Alters Sleep Architecture, Reduces Diurnal Corticosterone Levels, and Enhances Spatial Memory

Papale

Paul

Sawyer

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of transient depolarizing currents and play a critical role in the electrical signaling between neurons. A null mutation in the VGSC gene SCN8A, which encodes the transmembrane protein Na v 1.6, was identified previously in a human family. Heterozygous mutation carriers displayed a range of phenotypes, including ataxia, cognitive deficits, and emotional instability. A possible role for SCN8A was also proposed in studies examining the genetic basis of attempted suicide and bipolar disorder. In addition, mice with a Scn8a loss-of-function mutation (Scn8a

show abstract

“…Two other isoforms distributed throughout the nervous system, Na V 1.6 and Na V 1.8, have also been subjects of intense research concerning their role in the conduction of pain signals 2,[132][133][134][135] . Na V 1.9 had also shown an involvement in pain 136,137 , however a lack of Na V 1.9 assays and Na V 1.9 selective modulators have greatly hampered the isoform's therapeutic potential.…”

Section: Potassium Channelsmentioning

confidence: 99%

A pharmacological and transcriptomic approach to exploring novel pain targets

Yin¹

View full text Add to dashboard Cite

Ever since the discovery that mutations in the voltage-gated sodium channel 1.7 protein are responsible for human congenital insensitivity to pain, the voltage-gated sodium channel (Na V ) family of ion channels has been the subject of intense research with the hope of discovering novel analgesics. We now know that Na V 1.7 deletion in select neuronal populations yield different phenotypes, with the deletion of Na V 1.7 in all sensory neurons being successful at abolishing mechanical and heat-induced pain. However, it is rapidly becoming apparent that a number of pain syndromes are not modulated by Na V 1.7 at all, such as oxaliplatin-mediated neuropathy. It is particularly interesting to note that the loss of Na V 1.7 function is also associated with the selective inhibition of pain mediated by specific stimuli, such as that observed in burn-induced pain where Na V 1.7 gene knockout abolished thermal allodynia but did not affect mechanical allodynia. Accordingly, significant interests exist in delineating the contribution of other Na V isoforms in modality-specific pain pathways. Two other isoforms, Na V 1.6 and Na V 1.8, are now specifically implicated in some Na V 1.7-independent conditions such as oxaliplatin-induced cold allodynia. Such selective contributions of specific ion channel isoforms to pain highlight the need to discover other putative protein targets involved in mediating nociception.The aim of my work is therefore to discover selective molecular inhibitors of Na V 1.6 and Na V 1.8, to find useful cell models for peripheral nociceptors, to investigate the roles of Na V 1.6 and Na V 1.8 in an animal model of burn-induced pain, and to screen for putative new targets for analgesia in burn-related pain.Chapter 2 of this thesis describes activity-guided discovery of novel Na V 1.6 and Na V 1.8-modulting peptides from crude spider venoms. Crude venom from Poecilotheria metallica successfully reduced Na V 1.8-mediated voltage changes in HEK293-expressing cells. A new Na V 1.8-inhibitory peptide was sequenced from the venom and named Pme1a. However, Pme1a exhibited TRPV1 agonist activity and induced nocifensive behaviours, such as paw licking, after injection into the hind paws of mice, indicating the peptide was not a selective Na V 1.8 modulator and was unsuitable as a tool for Na V 1.8 investigation.iii With the unsuccessful exploration of spider venoms for new specific inhibitors, I then investigated in vitro cell models as tools to research specific nociceptor subtypes that express Na V 1.6 or Na V 1.8. In Chapter 3, I provide the first complete transcriptome of three common in vitro neuronal cell lines (SH-SY5Y, F-11, and ND7/23) to examine whether they were appropriate for investigating the functions of Na V 1.6 and Na V 1.8, and to identify if the cell lines resemble in vivo dorsal root ganglion (DRG) neuronal subclasses. The three cell lines examined all expressed proteins belonging to similar pathways and of similar proportions to native DRG neurons. However, they did not express any ce...

show abstract

Functional properties and differential neuromodulation of Nav1.6 channels

Cited by 116 publications

References 86 publications

Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

Dysfunction of the Scn8a Voltage-gated Sodium Channel Alters Sleep Architecture, Reduces Diurnal Corticosterone Levels, and Enhances Spatial Memory

A pharmacological and transcriptomic approach to exploring novel pain targets

Contact Info

Product

Resources

About