A Structural Framework for the Polymodal Pain Sensor TRPV1

Abstract

TRPV1 is an important polymodal cellular sensor for heat, capsaicin, and other noxious stimuli. How the channel is activated by diverse physical and chemical stimuli remains largely unknown. Structural information is critical for mechanistic investigation but is currently lacking for TRPV1 and its homologs. In order to provide a structural framework for the study of TRPV1 gating mechanism, we have first modeled the transmembrane region in both the closed and open states using the Rosetta method. Reliability of predicted structural models is supported by results from a combination of mutagenesis, fluorescence imaging and patch-clamp recording tests. We found that while the overall predicted structural architectures resemble those of other six-transmembrane tetrameric cation channels, there are a number of interesting unique structural features that may contribute to capsaicin sensitivity, coupling of conformational changes in the turret and other extracellular structures to the pore, as well as pore dilation upon activation. Extending these modeling efforts to the intracellular regions further indicated potential structural elements that may mediate subunit assembly and modulation by intracellular factors. Therefore, our model has setup a framework for further investigation of the molecular events that lead to TRPV1 activation.