Figure 10

A plausible model depicting the importance of Arg-cholesterol interaction and loop hydration in TRPV1 channel gating. The transmembrane helices and unstructured loops are mostly occupied in the core hydrophobic lipid bilayer (~thickness of 30 Å) and both side lipid-water interface regions (~thickness of 6A) respectively. The relative amount of free water is much less in LWI regions. Arg-cholesterol interaction in LI region preferably stabilizes TRPV1 in closed conformation and loss of this interaction possibly decreases the activation energy and thus increases the open probability and spontaneous opening of TRPV1. Phosphorylation at the loop residues induces more hydration of the loop regions and thereby can sensitize TRPV1. Similarly, substitution of Arg with other amino acids or cholesterol depletion results in loss of this interaction resulting in unwanted spontaneous activation. Cholesterol saturation and/or presence of other sterols may strengthen this interaction and therefore stabilize the closed conformation resulting in requirement of more activation energy and/or delayed channel opening. Cold-blooded and warm-blooded animals share inverse relationship with the levels of Arg present in lipid-water interface and cholesterol in membrane. Such relationship might be crucial for thermo-gating behaviour of TRPV1 in cold-blooded and warm-blooded animals.