Tmem100 Is a Regulator of TRPA1-TRPV1 Complex and Contributes to Persistent Pain

Abstract

SUMMARY TRPA1 and TRPV1 are crucial pain mediators, but how their interaction contributes to persistent pain is unknown. Here, we identify Tmem100 as a potentiating modulator of TRPA1-V1 complexes. Tmem100 is co-expressed and forms a complex with TRPA1 and TRPV1 in DRG neurons. Tmem100-deficient mice show a reduction in inflammatory mechanical hyperalgesia and TRPA1- but not TRPV1-mediated pain. Single-channel recording in a heterologous system reveals that Tmem100 selectively potentiates TRPA1 activity in a TRPV1-dependent manner. Mechanistically, Tmem100 weakens the association of TRPA1 and TRPV1, thereby releasing the inhibition of TRPA1 by TRPV1. A Tmem100 mutant, Tmem100-3Q, exerts the opposite effect, i.e., it enhances the association of TRPA1 and TRPV1 and strongly inhibits TRPA1. Strikingly, a cell-permeable peptide (CPP) containing the C-terminal sequence of Tmem100-3Q mimics its effect and inhibits persistent pain. Our study unveils a context-dependent modulation of the TRPA1-V1 complex, and Tmem100-3Q CPP is a promising pain therapy.

Nocistatin sensitizes TRPA1 channels in peripheral sensory neurons

“…25 It is noteworthy that a large subset of capsaicin-sensitive TRPV1-positive sensory neurons also expresses TRPA1 channels. 10,20 However, despite the apparent co-expression of both channels, cellular responses to TRPV1 activation were unaffected by Nocistatin in our experiments arguing for a certain degree of specificity of the observed TRPA1 sensitization by Nocistatin. Therefore, we propose TRPA1 as a hitherto unknown target of Nocistatin in the peripheral nervous system.…”

“…10,20 Therefore, we assessed TRPV1-dependent calcium influx, as well. Nocistatin did not change calcium responses elicited by low doses of capsaicin (CAPS; 0.1 mM), suggesting similar TRPV1-dependent calcium influx as in vehicle-treated controls (Fig.…”

“…Tmem100 has been shown to associate with TRPA1 and TRPV1 in sensory neurons where it potentiates TRPA1 activity in a TRPV1-dependent manner. 10 Given the crucial role of TRPA1 in nociception and pain, further exploration of molecular mechanisms regulating TRPA1 is highly relevant to understanding its function in both, physiological and pathological conditions. Here, we provide evidence that the neuropeptide Nocistatin sensitizes TRPA1-mediated cellular calcium responses in DRG neurons.…”

Molecules empowering animals to sense and respond to temperature in changing environments

“…Deciphering the role of a given TRP channel in thermosensation is complicated by several factors, including the fact that TRP channels integrate many signals [7] and interact with other proteins, including other TRP channels [8,9]. These factors affect interpretation of experiments performed in vivo and in heterologous systems, which are often somewhat responsive to temperature themselves [10].…”

“…TRPV1 and TRPM8 are two TRP channels widely believed to serve this function. They are expressed in thermosensory neurons, are required for normal behavioral responses to thermal stimulation, and confer extraordinary temperature sensitivity on heterologous cells [6].Deciphering the role of a given TRP channel in thermosensation is complicated by several factors, including the fact that TRP channels integrate many signals [7] and interact with other proteins, including other TRP channels [8,9]. These factors affect interpretation of experiments performed in vivo and in heterologous systems, which are often somewhat responsive to temperature themselves [10].…”