Gain-of-function mutation in SCN11A causes itch and affects neurogenic inflammation and muscle function in Scn11a +/L799P mice

摘要

Mutations in the genes encoding for voltage-gated sodium channels cause profound sensory disturbances and other symptoms dependent on the distribution of a particular channel subtype in different organs. Humans with the gain-of-function mutation p . Leu811Pro in SCN11A (encoding for the voltage-gated Na v 1.9 channel) exhibit congenital insensitivity to pain, pruritus, self-inflicted injuries, slow healing wounds, muscle weakness, Charcot-like arthropathies, and intestinal dysmotility. As already shown, knock-in mice ( Scn11a +/L799P ) carrying the orthologous mutation p . Leu799Pro replicate reduced pain sensitivity and show frequent tissue lesions. In the present study we explored whether Scn11a +/L799P mice develop also pruritus, muscle weakness, and changes in gastrointestinal transit time. Furthermore, we analyzed morphological and functional differences in nerves, skeletal muscle, joints and small intestine from Scn11a +/L799P and Scn11a +/+ wild type mice. Compared to Scn11a +/+ mice, Scn11a +/L799P mice showed enhanced scratching bouts before skin lesions developed, indicating pruritus. Scn11a +/L799P mice exhibited reduced grip strength, but no disturbances in motor coordination. Skeletal muscle fiber types and joint architecture were unaltered in Scn11a +/L799P mice. Their gastrointestinal transit time was unaltered. The small intestine from Scn11a +/L799P showed a small shift towards less frequent peristaltic movements. Similar proportions of lumbar dorsal root ganglion neurons from Scn11a +/L799P and Scn11a +/+ mice were calcitonin gene-related peptide (CGRP-) positive, but isolated sciatic nerves from Scn11a +/L799P mice exhibited a significant reduction of the capsaicin-evoked release of CGRP indicating reduced neurogenic inflammation. These data indicate important Na v 1.9 channel functions in several organs in both humans and mice. They support the pathophysiological relevance of increased basal activity of Na v 1.9 channels for sensory abnormalities (pain and itch) and suggest resulting malfunctions of the motor system and of the gastrointestinal tract. Scn11a +/L799P mice are suitable to investigate the role of Na v 1.9, and to explore the pathophysiological changes and mechanisms which develop as a consequence of Na v 1.9 hyperactivity.