Mapping protein interactions of sodium channel Na
            <sub>V</sub>
            1.7 using epitope‐tagged gene‐targeted mice

Kanellopoulos, Alexandros; Koenig, Jennifer; Huang, Honglei; Pyrski, Martina; Millet, Queensta; Lolignier, Stéphane; Morohashi, Toru; Gossage, Samuel J; Jay, Maude; Linley, John E.; Baskozos, Georgios; Kessler, Benedikt M.; Cox, James J.; Dolphin, Annette; Zufall, Frank; Wood, John N.; Zhao, Jing

doi:10.15252/embj.201796692

Cited by 61 publications

(44 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pert and Snyder showed the influence of sodium on opioid receptor activity in 1974, demonstrating that increased sodium concentrations caused diminished agonist binding 30 . Intracellular sodium levels may control this process 31 and the proximity of Nav1.7 channels to opioid receptors may influence sodium occupancy of these GPCRs 32 .…”

Section: Discussionmentioning

confidence: 99%

Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors

Pereira¹,

Millet²,

Aramburu³

et al. 2018

Wellcome Open Res

Self Cite

View full text Add to dashboard Cite

Background: Functional deletion of the Scn9a (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors involved in this form of analgesia. We also examined the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the Penk gene. Methods: We used specific µ-, δ- and κ-opioid receptor antagonists alone or in combination to examine which opioid receptors were necessary for Nav1.7 loss-associated analgesia in mouse behavioural assays of thermal pain. We also used µ- and δ-opioid receptor null mutant mice alone and in combination in behavioural assays to examine the role of these receptors in Nav1.7 knockouts pain free phenotype. Finally, we examined the levels of Penk mRNA in Nfat5-null mutant mice, as this transcription factor binds to consensus sequences upstream of the Penk gene. Results: The pharmacological block or deletion of both µ- and δ-opioid receptors was required to abolish Nav1.7-null opioid-related analgesia. κ-opioid receptor antagonists were without effect. Enkephalins encoded by the Penk gene are upregulated in Nav1.7 nulls. Deleting Nfat5, a transcription factor with binding motifs upstream of Penk, induces the same level of enkephalin mRNA expression as found in Nav1 .7 nulls, but without consequent analgesia. These data confirm that a combination of events linked to Scn9a gene loss is required for analgesia. Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in Nav1.7-null mouse and human mutants. Conclusions: These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development.

show abstract

Section: Discussionmentioning

confidence: 99%

Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors

Pereira¹,

Millet²,

Aramburu³

et al. 2018

Wellcome Open Res

Self Cite

View full text Add to dashboard Cite

show abstract

“…Kanellopoulos and colleagues have demonstrated that LAT1 interacts with the sodium channel Nav1.7 ( Kanellopoulos et al, 2018 ) ( Fig. 2 ).…”

Section: Hypoxia and Cancermentioning

confidence: 99%

“…Among other interactions, LAT1 has been reported to interact with channels with demonstrable links to pain, particularly a subtype of the voltage-gated potassium (Kv1.1) ( Baronas et al, 2018 ) and the voltage-gated sodium channels Nav1.7 ( Kanellopoulos et al, 2018 ).…”

Section: Hypoxia and Cancermentioning

confidence: 99%

Putative roles of SLC7A5 (LAT1) transporter in pain

Alles

Gómez

Moutal

et al. 2020

Neurobiology of Pain

View full text Add to dashboard Cite

Highlights Large amino acid transporter 1 (LAT1, SLC7A5), is an essential amino acid transporter. Expressed in the DRG and spinal cord, circumstantial evidence supports a tenous link for LAT1 in pain. LAT1 binds to voltage-gated ion channels involved in pain. LAT1 mediates the influx of gabapentin and pregabalin, two first-line neuropathic pain drugs. We hypothesize that LAT1 expressed in nociceptive pathways may be a viable new target in pain.

show abstract

“…In a very recent proteomics study, β3 was identified as a strong interaction partner for Nav1.7 in mice (Kanellopoulos et al 2018). Because of the high degree of sequence conservation and structural similarity of β1 and β3 subunits, one might expect similar mechanoprotective properties of β3.…”

Section: Discussionmentioning

confidence: 99%

β1 subunit stabilises sodium channel Nav1.7 against mechanical stress

Körner

Meents

Machtens

et al. 2018

The Journal of Physiology

View full text Add to dashboard Cite

Voltage-gated sodium channels are key players in neuronal excitability and pain signalling. Precise gating of these channels is crucial as even small functional alterations can lead to pathological phenotypes such as pain or heart failure. Mechanical stress has been shown to affect sodium channel activation and inactivation. This suggests that stabilising components are necessary to ensure precise channel gating in living organisms. Here, we show that mechanical shear stress affects voltage dependence of activation and fast inactivation of the Nav1.7 channel. Co-expression of the β1 subunit, however, protects both gating modes of Nav1.7 against mechanical shear stress. Using molecular dynamics simulation, homology modelling and site-directed mutagenesis, we identify an intramolecular disulfide bond of β1 (Cys21-Cys43) which is partially involved in this process: the β1-C43A mutant prevents mechanical modulation of voltage dependence of activation, but not of fast inactivation. Our data emphasise the unique role of segment 6 of domain IV for sodium channel fast inactivation and confirm previous reports that the intracellular process of fast inactivation can be modified by interfering with the extracellular end of segment 6 of domain IV. Thus, our data suggest that physiological gating of Nav1.7 may be protected against mechanical stress in a living organism by assembly with the β1 subunit.

show abstract

Mapping protein interactions of sodium channel Na _V 1.7 using epitope‐tagged gene‐targeted mice

Cited by 61 publications

References 71 publications

Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors

Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors

Putative roles of SLC7A5 (LAT1) transporter in pain

β1 subunit stabilises sodium channel Nav1.7 against mechanical stress

Contact Info

Product

Resources

About

Mapping protein interactions of sodium channel Na V 1.7 using epitope‐tagged gene‐targeted mice

Cited by 61 publications

References 71 publications

Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors

Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors

Putative roles of SLC7A5 (LAT1) transporter in pain

β1 subunit stabilises sodium channel Nav1.7 against mechanical stress

Contact Info

Product

Resources

About

Mapping protein interactions of sodium channel Na _V 1.7 using epitope‐tagged gene‐targeted mice