FXYD6 promotes thermal nociception by regulating TRPV1

Abstract

FXYD6, an unnecessary auxiliary subunit of Na+,K+-ATPase, is expressed in the nervous system. However, its functions remain largely unclear. In the present study, we find that FXYD6 is involved in the thermal nociception. FXYD6 was mainly expressed in small-diameter DRG neurons expressing transient receptor potential channel V1 (TRPV1). In the SNS-Cre/ Fxyd6F/F mice, loss of FXYD6 in these sensory neurons impaired the behavioral responses to noxious heat stimulus and intraplantar injection of capsaicin. The capsaicin-induced and TRPV1-mediated currents were decreased in the FXYD6–deficient DRG neurons. Heterologous expression of FXYD6 could increase the TRPV1 capsaicin-sensitive currents in HEK293 cells. Furthermore, we found that the negatively charged PGDEE motif in C-terminal of FXYD6 is required for the FXYD6/TRPV1 interaction and FXYD6-mediated enhancement of TRPV1. Disrupting the FXYD6/TRPV1 interaction with the TAT-PGDEE peptide could elevate the threshold of thermal nociception. Therefore, FXYD6 maintains the thermal nociception via interacting with TRPV1 channel in nociceptors.

Identification of FXYD6 as the novel biomarker for glioma based on differential expression and DNA methylation

“…But on the other hand, LGG patients generally have a longer survival, making it possible that FXYD6 affects immune‐related functions to improve patient outcomes. Furthermore, according to our previous studies, FXYD6 co‐expresses with TRPV1 in Gal + type small‐diameter DRG neurons, and could interact with TRPV1 channel by the highly negatively charged C‐terminal PGDEE motif, and thus to increase its capsaicin‐sensitive currents in mice 14,18 . As to TRPV1, the one 2021 Nobel molecule, it was studied well and most known for its role in somatosensation, especially in noxious heat 54 .…”

“…The samples were loaded for SDS‐PAGE, transferred, probed with antibodies, and visualized with enhanced chemiluminescence (GE Amersham Imager600). The primary antibodies against FXYD6 (1:1000, Rb, Proteintech, SAB1101623, and 1:500, Rb, previous paper 14 ), and Actin (1:100000, Mo, Chemicon, MAB1501), and corresponding horseradish peroxidase‐conjugated secondary antibody were used.…”

“…According to single‐cell RNA‐sequencing, Fxyd6 is mainly distributed in small‐diameter Gal cluster and Th cluster DRG neurons, the primary sensory neurons, suggesting the distinct functions of FXYD6 in somatosensation 18,19 . In fact, FXYD6 could bind to TRPV1 channel and increase capsaicin‐induced current in Gal cluster DRG neurons, thus promoting thermal nociception 14 . Besides, some studies of FXYD6 have reported the specific candidate single nucleotide polymorphisms in schizophrenia, 20,21 the changed expression patterns in Alzheimer's disease (AD) Tg2576 mice, 22 and the GWAS analysis in alcohol addiction 23 .…”

“… 3 , 4 , 5 , 6 FXYD6 is widely distributed in different tissues and organs, and related to different cancers, such as hepatocellular carcinoma, pancreatic cancer, and cholangiocarcinoma. 7 , 8 , 9 , 10 In nervous system, FXYD6 is found to be expressed in Type II taste bud cells, 11 , 12 Type II spiral ganglion neurons, 13 two clusters of dorsal root ganglion (DRG) neurons, 14 almost all subnuclei of parabrachial nucleus, 15 as well as cerebellum and hippocampus. 16 , 17 According to single‐cell RNA‐sequencing, Fxyd6 is mainly distributed in small‐diameter Gal cluster and Th cluster DRG neurons, the primary sensory neurons, suggesting the distinct functions of FXYD6 in somatosensation.…”

“… 18 , 19 In fact, FXYD6 could bind to TRPV1 channel and increase capsaicin‐induced current in Gal cluster DRG neurons, thus promoting thermal nociception. 14 Besides, some studies of FXYD6 have reported the specific candidate single nucleotide polymorphisms in schizophrenia, 20 , 21 the changed expression patterns in Alzheimer's disease (AD) Tg2576 mice, 22 and the GWAS analysis in alcohol addiction. 23 In a word, FXYD6 assumes significant functions in both physiological and pathological conditions, especially within the neurological system.…”