TRPV4: a thermosensitive non-selective cation channel
TRPV4 is a member of TRPV family and is a Ca2+-permeable nonselective cation channel. It is a fascinating non-selective ion channel (favors divalent ions more than monovalent ions) with polymodal gating behavior that can be activated by temperature, chemical ligands, osmolarity and mechanical force. While structures exist for both open and close TRPV4, the activation mechanism is still largely unknown.
In this project,, I am trying to combine experiments and atomistic MD stimulations to probe the activation mechanism of TRPV4. First, I plan to determine the sensor (such as temperature-sensing element(s) and mechanic force-sensing element(s)) of TRPV4 by simulating the dynamics of TRPV4 WT and some important mutants (which behave special sensitivity) under different temperatures or surface tensions. Second, the sensor candidates will be further verified by experiments (like mutagenesis). Besides, the responses of the sensors as well as the coupling between the sensors and pore domain will be explored to elucidate the activation process through simulations and experimental validations.
Significance
Revealing the temperature sensing mechanism of TRPV4 provides new insights to understand its physiological roles and functionalities and also helps us to understand the pathogenesis of channelopathies and design targeting drugs.