*3.1. TRPV1–TMEM100–TRPA1 Interaction*

TRPV1 is co-expressed with TRPA1 in DRG neurons. Since TRPA1 activity is enhanced by intracellular calcium, it had been thought that calcium influx through TRPV1 activation could affect TRPA1 function. However, the TRPV1 entity reduces the probability of TRPA1 ion channel opening accelerated by mustard oil [92]. It appears that TRPA1-associated pain is normally reduced by TRPV1 expression, which may be prevented by TMEM100 [92]. TMEM100 is a small membrane protein, and its expression pattern highly overlaps with CGRP. Interestingly, TRPA1 almost co-localizes with TRPV1, TMEM100, and CGRP in DRG neurons (Figure 1). Together, TRPV1, TRPA1, and TMEM100 form a complex, and the interaction between TRPV1 and TRPA1 is suppressed by interposition of TMEM100. Furthermore, a mutant peptide of TMEM100 (T100-Mut) can permeate the plasma membrane and disturb correct binding of TMEM100, thereby inhibiting TRPA1-associated pain-related behavior. This may provide a novel strategy for reducing pain sensation.
