FGF13 Is Required for Histamine-Induced Itch Sensation by Interaction with Na_V1.7

Abstract

Itch can be induced by activation of small-diameter DRG neurons, which express abundant intracellular fibroblast growth factor 13 (FGF13). Although FGF13 is revealed to be essential for heat nociception, its role in mediating itch remains to be investigated. Here, we reported that loss of FGF13 in mouse DRG neurons impaired the histamine-induced scratching behavior. Calcium imaging showed that the percentage of histamine-responsive DRG neurons was largely decreased in FGF13-deficient mice; and consistently, electrophysiological recording exhibited that histamine failed to evoke action potential firing in most DRG neurons from these mice. Given that the reduced histamine-evoked neuronal response was caused by knockdown of FGF13 but not by FGF13A deficiency, FGF13B was supposed to mediate this process. Furthermore, overexpression of histamine Type 1 receptor H1R, but not H2R, H3R, nor H4R, increased the percentage of histamine-responsive DRG neurons, and the scratching behavior in FGF13-deficient mice was highly reduced by selective activation of H1R, suggesting that H1R is mainly required for FGF13-mediated neuronal response and scratching behavior induced by histamine. However, overexpression of H1R failed to rescue the histamine-evoked neuronal response in FGF13-deficient mice. Histamine enhanced the FGF13 interaction with Na V 1.7. Disruption of this interaction by a membrane-permeable competitive peptide, GST-Flag-Na V 1.7CT-TAT, reduced the percentage of histamine-responsive DRG neurons, and impaired the histamine-induced scratching, indicating that the FGF13/Na V 1.7 interaction is a key molecular determinant in the histamine-induced itch sensation. Therefore, our study reveals a novel role of FGF13 in mediating itch sensation via the interaction of Na V 1.7 in the peripheral nervous system.

A Heterozygous Variant of FGF13 Caused X-Linked Developmental and Epileptic Encephalopathy 90 in a Chinese Family

“…FGF13 was confirmed to function as an auxiliary protein that interacted with voltage-gated Na+ channels [Dong et al, 2020;Wang et al, 2011;Yang et al, 2017]. Disruption of FGF13 was demonstrated to cause genetic epilepsy and febrile seizures plus (GEFS+) in 2015 [Puranam et al, 2015].…”

FGF13 enhances the function of TRPV1 by stabilizing microtubules and regulates acute and chronic itch

“…25 As more studies confirm the involvement of FGF13 in numerous human disorders, determining the association between FGF13 and diseases becomes increasingly relevant. Although a previous study has reported that FGF13 is required in histamine-induced pruritus by interacting with Na V 1.7, 33 the association between the modulatory effects of FGF13 on itch sensation and TRP channel function has not been explored. This study identified a new mechanism of FGF13 involvement F I G U R E 7 A graphical diagram of the mechanism by which FGF13 modulated TRPV1 function by stabilizing microtubules and regulating acute and chronic itch.…”

“…Small-diameter neurons (Cm < 42 pF) were selected for whole-cell patch clamp recording in voltage-and currentclamp configurations, as described previously. 33,34 All electrophysiological experiments were performed at room temperature (22-25°C).…”

Somatosensory neurons express specific sets of lincRNAs, and lincRNA CLAP promotes itch sensation in mice

“…The Ca 2+ influx curve represented a normalized value of the ratio for fluorescent difference (Ft − F0) to basal fluorescence (F0). Cells were identified as responsive neuron based on the calcium elevation measured by the average ratio (340 nm/380 nm) after 10 s treatment by different drugs was 15% above baseline as previous study (Dong et al , 2020). Histamine (1 mM, Sigma), 5‐HT (100 μM, Tocris Bioscience), chloroquine (1 mM, Sigma), capsaicin (1 μM, Sigma), and KCl (80 mM, Sigma) were applied to DRG neurons to observe Ca 2+ influx.…”