The role of Nav1.9 and Nav1.1 in somatosensory perception
Embargo until
2019-12-01
Date
2018-10-01
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Publisher
Johns Hopkins University
Abstract
Voltage-gated sodium (NaV) channels are critical for the electrical signaling of excitable cells. Due to their importance in cellular signaling, mutations in these crucial proteins can lead to a cadre of different diseases and syndromes, such as severe painful neuropathies, seizures, cardiac arrhythmias, along with many other grave conditions. Here, we show that NaV1.1 and NaV1.9 are key players in transmitting visceral pain and itch, respectively. NaV1.1 is functional upregulated in chronic visceral hypersensitivity (CVH) mouse models, and inhibiting NaV1.1 with a NaV1.1-selective inhibitor leads to an attenuation of the visceral pain that develops in these IBS models. We also demonstrate that NaV1.9 is important for both histamine- and Mrgpr-dependent itch, and loss of NaV1.9 leads to a dramatic reduction in mice for both forms of itch. Furthermore, patients with a gain-of-function mutation in NaV1.9 experience severe pruritus caused by an enhanced excitability of MrgprA3+ neurons, as evidenced by our experiments. Together, we provide compelling evidence for the functional importance in the pain and itch field for two NaV channel subtypes.
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Keywords
pain, itch, nav1.9, n nav1.1, mrgpra3, histamine, IBS, visceral, DRG, gain-of-function, hyper excitable