Augmented Sodium Currents Contribute to the Enhanced Excitability of Small Diameter Capsaicin-Sensitive Sensory Neurons Isolated From <i>Nf1</i>+/− Mice

Wang, Yue; Duan, Jian-Hong; Hingtgen, Cynthia M.; Nicol, Grant D.

doi:10.1152/jn.01010.2009

Cited by 20 publications

(37 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, we demonstrated that small diameter capsaicin-sensitive sensory neurons isolated from mice with a heterozygous mutation of the Nf1 gene (coding for the protein neurofibromin) have augmented excitability compared to wildtype neurons (Wang et al, 2005). Consistent with this enhanced excitability, the peak current densities for both tetrodotoxin-sensitive and –resistant sodium currents (Wang et al, 2010a) as well as the expression of mRNA for specific sodium channel subtypes (Hodgdon et al, 2012) were significantly larger in Nf1 +/− sensory neurons. However, neither delayed rectifier nor A-type potassium currents were altered in Nf1 +/− neurons (Wang et al, 2010a).…”

Section: Introductionmentioning

confidence: 73%

“…Consistent with this enhanced excitability, the peak current densities for both tetrodotoxin-sensitive and –resistant sodium currents (Wang et al, 2010a) as well as the expression of mRNA for specific sodium channel subtypes (Hodgdon et al, 2012) were significantly larger in Nf1 +/− sensory neurons. However, neither delayed rectifier nor A-type potassium currents were altered in Nf1 +/− neurons (Wang et al, 2010a). Furthermore, stimulus-evoked release of the neuropeptides, substance P and calcitonin gene-related peptide (CGRP), was significantly higher from sensory neurons isolated from Nf1 +/− mice (Hingtgen et al, 2006).…”

Section: Introductionmentioning

confidence: 73%

“…The whole-cell patch-clamp recording technique was used as previously described (Wang et al 2010a). Neurons were bathed in normal Ringers of the following composition (mM): 140 NaCl, 5 KCl, 2 CaCl 2 , 1 MgCl 2 , 10 HEPES and 10 glucose, pH adjusted to 7.4 with NaOH.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

N-type calcium current, Cav2.2, is enhanced in small-diameter sensory neurons isolated from Nf1+/− mice

et al. 2014

Self Cite

View full text Add to dashboard Cite

Major aspects of neuronal function are regulated by Ca2+ including neurotransmitter release, excitability, developmental plasticity, and gene expression. We reported previously that sensory neurons isolated from a mouse model with a heterozygous mutation of the Nf1 gene (Nf1+/−) exhibited both greater excitability and evoked release of neuropeptides compared to wildtype mice. Furthermore, augmented voltage-dependent sodium currents but not potassium currents contribute to the enhanced excitability. To determine the mechanisms giving rise to the enhanced release of substance P and calcitonin gene-related peptide in the Nf1+/− sensory neurons, the potential differences in the total voltage-dependent calcium current (ICa) as well as the contributions of individual Ca2+ channel subtypes were assessed. Whole-cell patch-clamp recordings from small diameter capsaicin-sensitive sensory neurons demonstrated that the average peak ICa densities were not different between the two genotypes. However, by using selective blockers of channel subtypes, the current density of N-type (Cav2.2) ICa was significantly larger in Nf1+/− neurons compared to wildtype neurons. In contrast, there were no significant differences in L-, P/Q- and R-type currents between the two genotypes. Quantitative real-time PCR measurements made from the isolated but intact dorsal root ganglia indicated that N-type (Cav2.2) and P/Q-type (Cav2.1) Ca2+ channels exhibited the highest mRNA expression levels although there were no significant differences in the levels of mRNA expression between the genotypes. These results suggest that the augmented N-type (Cav2.2) ICa observed in the Nf1+/− sensory neurons does not result from genomic differences but may reflect post-translational or some other non-genomic modifications. Thus, our results demonstrate that sensory neurons from Nf1+/− mice, exhibit increased N-type ICa and likely account for the increased release of substance P and calcitonin gene-related peptide that occurs in Nf1+/− sensory neurons.

show abstract

Section: Introductionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 73%

See 1 more Smart Citation

N-type calcium current, Cav2.2, is enhanced in small-diameter sensory neurons isolated from Nf1+/− mice

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Strikingly, neurofibromatosis type-1 (NF1) patients, in whom neurofibromin is often mutated or truncated, experience idiopathic chronic pain for which opioids often fail to provide relief [106–109]. Observations of DRGs in Nf1 +/− haploinsufficient mice revealed augmented sodium (Na + ) current densities (both tetrodotoxin (TTX)-sensitive and TTX-resistant), alongside increased N-type Ca 2+ currents and enhanced stimulus-evoked release of glutamate, substance P, and CGRP [110–113]. Interestingly, treatment of Nf1 +/− DRGs with the aforementioned t-CBD3 inhibited both Cav2.2-mediated currents and CGRP release [98].…”

Section: Dysregulation Of Vgccs In Neuropathic Painmentioning

confidence: 99%

CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

Chew

Khanna

2018

Neuronal Signaling

View full text Add to dashboard Cite

Neuropathic pain represents a significant and mounting burden on patients and society at large. Management of neuropathic pain, however, is both intricate and challenging, exacerbated by the limited quantity and quality of clinically available treatments. On this stage, dysfunctional voltage-gated ion channels, especially the presynaptic N-type voltage-gated calcium channel (Cav2.2) and the tetrodotoxin-sensitive voltage-gated sodium channel (Nav1.7), underlie the pathophysiology of neuropathic pain and serve as high profile therapeutic targets. Indirect regulation of these channels holds promise for the treatment of neuropathic pain. In this review, we focus on collapsin response mediator protein 2 (CRMP2), a protein with emergent roles in voltage-gated ion channel trafficking and discuss the therapeutic potential of targeting this protein.

show abstract

“…In these neurons from Nf1 ϩ/Ϫ mice with reduced expression of neurofibromin, the increased excitability can be explained by a significant increase in sodium current density compared with WT neurons (Wang et al 2010). The stimulusevoked release of iCGRP is also enhanced in sensory neurons isolated from Nf1 ϩ/Ϫ mice compared with that from WT mice (Hingtgen et al 2006).…”

Section: Discussionmentioning

confidence: 94%

Reduced expression of SynGAP, a neuronal GTPase-activating protein, enhances capsaicin-induced peripheral sensitization

Duarte¹,

Duan²,

Nicol³

et al. 2011

Journal of Neurophysiology

View full text Add to dashboard Cite

Duarte DB, Duan JH, Nicol GD, Vasko MR, Hingtgen CM. Reduced expression of SynGAP, a neuronal GTPase-activating protein, enhances capsaicin-induced peripheral sensitization. J Neurophysiol 106: 309 -318, 2011. First published April 27, 2011 doi:10.1152/jn.00963.2010.-Synaptic GTPase-activating protein (SynGAP) is a neuronal-specific Ras/Rap-GAP that increases the hydrolysis rate of GTP to GDP, converting Ras/Rap from the active into the inactive form. The Ras protein family modulates a wide range of cellular pathways including those involved in sensitization of sensory neurons. Since GAPs regulate Ras activity, SynGAP might be an important regulator of peripheral sensitization and pain. Therefore, we evaluated excitability, stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP), and nociception from wildtype (WT) mice and those with a heterozygous mutation of the SynGAP gene (SynGAP ϩ/Ϫ ). Our results demonstrate that SynGAP is expressed in primary afferent sensory neurons and that the capsaicinstimulated CGRP release from spinal cord slices was two-fold higher from SynGAP ϩ/Ϫ mice than that observed from WT mouse tissue, consistent with an increase in expression of the capsaicin receptor, transient receptor potential cation channel subfamily V member 1 (TRPV1), in SynGAP ϩ/Ϫ dorsal root ganglia. However, there was no difference between the two genotypes in potassium-stimulated release of CGRP, the number of action potentials generated by a ramp of depolarizing current, or mechanical hypernociception elicited by intraplantar injection of capsaicin. In contrast, capsaicin-induced thermal hypernociception occurred at lower doses of capsaicin and had a longer duration in SynGAP ϩ/Ϫ mice than WT mice. These results provide the first evidence that SynGAP is an important regulator of neuropeptide release from primary sensory neurons and can modulate capsaicin-induced hypernociception, demonstrating the importance of GAP regulation in signaling pathways that play a role in peripheral sensitization.calcitonin gene-related peptide; capsaicin; dorsal root ganglia; thermal hypernociception

show abstract

Augmented Sodium Currents Contribute to the Enhanced Excitability of Small Diameter Capsaicin-Sensitive Sensory Neurons Isolated From Nf1+/− Mice

Cited by 20 publications

References 67 publications

N-type calcium current, Cav2.2, is enhanced in small-diameter sensory neurons isolated from Nf1+/− mice

N-type calcium current, Cav2.2, is enhanced in small-diameter sensory neurons isolated from Nf1+/− mice

CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

Reduced expression of SynGAP, a neuronal GTPase-activating protein, enhances capsaicin-induced peripheral sensitization

Contact Info

Product

Resources

About