Contributions of the Transmembrane Domain to Heat Activation of Human TRPV1

Abstract

Temperature sensation and regulation are crucial physiological processes in biology. Transient receptor potential vanilloid-1 (TRPV1) is a highly studied cation channel that is largely responsible for thermosensation, as well as nociception. Along with being activated by high temperatures, the receptor is also activated by capsaicin, the pungent vanilloid compound in chili peppers. Chemical ligand binding has been well-characterized functionally and structurally, but despite significant interest, the molecular mechanisms behind thermosensation have remained unclear. Studies outside of our lab have indicated that the human TRPV1 pore domain (hV1-PD) is a factor in the thermosensitivity of human TRPV1, and additional studies conducted within our lab of the human TRPV1 sensing domain (hV1-SD) have shown that this domain contributes significantly to the heat activation mechanism of human TRPV1. These data illuminate a need for further investigation of human TRPV1 to elucidate the molecular underpinnings of thermosensation. Furthermore, these studies point to the human TRPV1 transmembrane domain (hV1-TMD) as being a critical region within the channel responsible for heat activation. This research utilizes a variety biophysical techniques including negative-stain electron microscopy (EM) and solution nuclear magnetic resonance (NMR) spectroscopy to probe the hV1-TMD for its contributions to heat activation of the human TRPV1 channel.