Turning TRPV1 off

How can something like capsaicin of chili pepper fame/infame hurt like bloody hell and then have analgesic properties? We have covered the TRP family of Ca²⁺ channels on a page on this site. Nature has given us a negative feedback mechanism byway of a small Ca²⁺ modulated protein that we call calmodulin, of CaM for short. We have known that Ca²⁺CaM binds to the N-terminus region also involving the 1st ankyrin repeat since 2004. [1]

A 2012 study was able to crystalized the entire Ca²⁺CaM molecule with a C-terminal fragment of TrpV1. {2] technical difficulties prevented them from crystalizing Ca²⁺CaM with ankyrin repeat domains. They did determine that the C-terminus lobe of Ca²⁺CaM binds the repeats. [2] And no, the extended Ca²⁺CaM cannot cross link the N-terminus and C-terminus of CrtV1. [2] The idea is that once enough calcium has entered the cell Ca²⁺CaM binds to TrpV1 and turns the channel off. Nature has given more ways of turning off TrpV1 with Ca²⁺ feedback inhibition. Another post!

References

1. Rosenbaum T, Gordon-Shaag A, Munari M, Gordon SE.(2004) Ca2+/calmodulin modulates TRPV1 activation by capsaicin. J Gen Physiol. 2004 Jan;123(1):53-62. PMC free article
2. Lau, Sze-Yi et al. “Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel.” The Journal of general physiology vol. 140,5 (2012): 541-55.