A disease mutation reveals a role for NaV1.9 in acute itch

Salvatierra, Juan; Diaz-Bustamante, Marcelo; Meixiong, James; Tierney, Elaine; Dong, Xinzhong; Bosmans, Frank

doi:10.1172/jci122481

Cited by 44 publications

(54 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with previous studies, we show that a deletion or inhibition of one Na V channel is not sufficient to fully abolish scratching in mice 28,[30][31][32][33] . The contribution of several Na V channels to acute itch signalling of different stimuli, shown here, supports the suggestion that a simultaneous inhibition of different Na V channels is required to reach full abolishment.…”

Section: Discussionsupporting

confidence: 92%

“…Taken together with our behavioural data, we suggest that Na V 1.9 modulates the transformation of acute itch stimuli, lowering the threshold to action potential generation. The effects observed in Na V 1.9 −/− are less prominent than observations recently made by Salvatierra et al, who showed a reduction of scratch behaviour in Na V 1.9 knockout mice upon histamine, chloroquine and BAM8-22 when applying the substances subcutaneously 28 . While the nerve endings of primary sensory neurons largely terminate in the epidermis, other cellular players of itch signalling such as mast cells are distributed in the corium 50 which potentially modulate neuronal activation when applying pruritogens subcutaneously compared to an intradermal application.…”

Section: Discussioncontrasting

confidence: 65%

“…Several subtype-specific Na V inhibitors have lately entered clinical trials for different pain treatments [23][24][25] .Additionally, recent studies presented an important role of Na V 1.7-1.9 in itch signalling. Case studies revealed that gain-of-function mutations in these Na V channels can cause paroxysmal itch in affected patients [26][27][28][29] . Corresponding inhibitory studies analysed the role of Na V subtypes in itch signalling.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Kühn

Kappes

Wolf

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (Na V ) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, Na V 1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing Na V -specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, β-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in Na V channel-mediated itch signalling. Na V 1.7 −/− showed substantial scratch reduction mainly towards strong pruritogens. Na V 1.8 −/− impaired histamine and 5-HT-induced scratching while Na V 1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of Na V 1.7 and indicated an overall contribution of na V 1.9. Beside the proposed general role of Na V 1.7 and 1.9 in itch signalling, scrutiny of time courses suggested Na V 1.8 to sustain prolonged itching. Therefore, Na V 1.7 and 1.9 may represent targets in pruritus therapy.Pruritus, commonly also referred to as itch, can appear as agonizing symptom of dermatological, systemic and psychogenic disorders 1 . Despite its high impact on the quality of life, treatment options remain limited. One obstacle in the development of new drugs arises from the diversity of signalling pathways triggering itch. Aside histamine, which was the first known pruritogen 2,3 , pruritus can be elicited by various histamine-independent pruritogens with diverse chemical structures acting on a wide range of receptors. A major role in histamine-independent itch signalling can be attributed to Mas-related G protein-coupled receptors (MRGPR). This family of G protein-coupled receptors (GPCRs) mediates acute scratch behaviour towards pruritogens such as bovine adrenal medulla 8-22 peptide (BAM8-22) 4 , chloroquine 5 , β-alanine 6 and the tethered PAR2 ligand SLIGRL 7 . Additionally, pruritogens like 5-hydroxytryptamine (5-HT) 8 , and lysophosphatidic acid (LPA) 9 signal via activation of their specific receptors.Pruritogens can activate GPCRs located on nerve endings of unmyelinated primary sensory neurons, resulting in a rise of cytosolic calcium levels both via the inositol phospholipid signalling pathway 10-13 and via transient receptor potential ion channels (TRP) 14 . Upon membrane depolarization, voltage-gated sodium channels (Na V ) are opened, triggering the initiation and propagation of action potentials. The function of Na V channels is determined by the pore-forming alpha-subunit of which nine subtyp...

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 65%

mentioning

confidence: 99%

See 1 more Smart Citation

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Kühn

Kappes

Wolf

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…These channels regulate neuronal excitability and action potential propagation by altering resting membrane potential and inactivation thresholds. Numerous gain-of-function mutations that serve to increase neuronal excitability have been identified as causing neuropathic itch in patients [ 27 , 28 , 29 , 30 , 31 ]. For example, three patients with paroxysmal bouts of severe itch affecting the trunk and upper extremities were found to have abnormal sensory thresholds due to a Na v 1.7 I739V mutation [ 29 ].…”

Section: Neuropathic Itch and Channelopathiesmentioning

confidence: 99%

“…For example, three patients with paroxysmal bouts of severe itch affecting the trunk and upper extremities were found to have abnormal sensory thresholds due to a Na v 1.7 I739V mutation [ 29 ]. Similarly, an additional patient complaining of severe, unrelenting itch, was identified as harboring a mutation in a different channel, Na v 1.9 L811P [ 31 ]. In the described patients, severe, neuropathic itch occurred in the absence of any known itch-associated pathology or even overt damage to the nervous system.…”

Section: Neuropathic Itch and Channelopathiesmentioning

confidence: 99%

Neuropathic Itch

Meixiong

Dong

Weng

2020

Cells

Self Cite

View full text Add to dashboard Cite

Neurologic insults as varied as inflammation, stroke, and fibromyalgia elicit neuropathic pain and itch. Noxious sensation results when aberrantly increased afferent signaling reaches percept-forming cortical neurons and can occur due to increased sensory signaling, decreased inhibitory signaling, or a combination of both processes. To treat these symptoms, detailed knowledge of sensory transmission, from innervated end organ to cortex, is required. Molecular, genetic, and behavioral dissection of itch in animals and patients has improved understanding of the receptors, cells, and circuits involved. In this review, we will discuss neuropathic itch with a focus on the itch-specific circuit.

show abstract

Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy

2019

View full text Add to dashboard Cite

IMPORTANCE Small-fiber polyneuropathy involves preferential damage to the thinly myelinated A-delta fibers, unmyelinated C sensory fibers, or autonomic or trophic fibers. Although this condition is common, most patients still remain undiagnosed and untreated because of lagging medical and public awareness of research advances. Chronic bilateral neuropathic pain, fatigue, and nausea are cardinal symptoms that can cause disability and dependence, including pain medication dependence.OBSERVATIONS Biomarker confirmation is recommended, given the nonspecificity of symptoms. The standard test involves measuring epidermal neurite density within a 3-mm protein gene product 9.5 (PGP9.5)-immunolabeled lower-leg skin biopsy. Biopsies and autonomic function testing confirm that small-fiber neuropathy not uncommonly affects otherwise healthy children and young adults, in whom it is often associated with inflammation or dysimmunity. A recent meta-analysis concluded that small-fiber neuropathy underlies 49% of illnesses labeled as fibromyalgia. Initially, patients with idiopathic small-fiber disorders should be screened by medical history and blood tests for potentially treatable causes, which are identifiable in one-third to one-half of patients. Then, secondary genetic testing is particularly important for familial and childhood cases. Treatable genetic causes include Fabry disease, transthyretin and primary systemic amyloidosis, hereditary sensory autonomic neuropathy-1, and ion-channel mutations. Immunohistopathologic evidence suggests that small-fiber dysfunction and denervation, especially of blood vessels, contributes to diverse symptoms, including postexertional malaise, postural orthostatic tachycardia, and functional gastrointestinal distress. Preliminary evidence implicates acute or chronic autoreactivity in some cases, particularly in female patients and otherwise healthy children and young adults. Different temporal patterns akin to Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy have been described; here, corticosteroids and immunoglobulins, which are often efficacious for inflammatory neuropathic conditions, are increasingly considered.CONCLUSIONS AND RELEVANCE Because small fibers normally grow throughout life, improving contributory conditions may permit regrowth, slow progression, and prevent permanent damage. The prognosis is often hopeful for improving quality of life and sometimes for abatement or resolution, particularly in the young and otherwise healthy individuals. Examples include diabetic, infectious, toxic, genetic, and inflammatory causes. The current standard of care requires prompt diagnosis and treatment, particularly in children and young adults, to restore life trajectory. Consensus diagnostic and tracking metrics should be established to facilitate treatment trials.

show abstract

A disease mutation reveals a role for NaV1.9 in acute itch

Cited by 44 publications

References 57 publications

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Neuropathic Itch

Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy

Contact Info

Product

Resources

About