In a study published in Journal of Neuroscience, the researchers from Dr. ZHANG Xu’s Lab at the Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology of the Chinese Academy of Sciences (CAS), and from Dr. BAO Lan’s Lab at Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Biology of CAS, revealed a novel role of fibroblast growth factor (FGF)13 in mediating itch sensation via the interaction with Na_V1.7 in the peripheral nervous system.  

FGF13 is expressed abundantly in the neurons of dorsal root ganglion (DRG). Activation of small DRG neurons was found to generate multiple types of somatosensation, including pain and itch.  

Previous study has examined the functional role of FGF13 in somatosensation using conditional FGF13-deficient mice in small DRG neurons. These mice lost heat nociception but exhibited normal responses to noxious mechanical stimuli. However, it’s unclear whether FGF13 is involved in the itch sensation. 

In this study, the researchers found 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 showed that histamine failed to evoke action potential firing in most DRG neurons from these mice.  

Furthermore, the researchers found that the 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_V1.7. Disruption of this interaction by a membrane-permeable competitive peptide, GST-Flag-Na_V1.7CT-TAT, reduced the percentage of histamine-responsive DRG neurons, and impaired the histamine-induced scratching, indicating that the FGF13/Na_V1.7 interaction is a key molecular determinant in the histamine-induced itch sensation.  

The researchers also found that FGF13 was involved in 5-hydroxytryptamine (5-HT) and chloroquine-induced scratching behavior and hapten 1-fluoro-2,4-dinitrobenzene (DNFB)-induced chronic itch. 

Histamine activates small DRG neurons that express H1R. In the presence of FGF13, activation of H1R leads to subsequent activation of Na_V1.7, AP firing, and scratching behavior. (Image by CEBSIT)