A possible molecular mechanism for TRPV1 activation. The channel is shown in gray; water in the pore and peripheral cavities in cyan and blue, respectively; the conserved asparagine N676 in S6 in green; the membrane in purple (extra and intra denote extra- and intracellular solutions). In the capsaicin-bound closed state, the peripheral cavities host several water molecules, while the pore is partially dehydrated; N676 projects its side chain toward the peripheral cavities. Upon application of an activating stimulus, the peripheral cavities dehydrate, an event that correlates with the rotation of N676 toward the pore. The presence of a hydrophilic side chain inside the pore promotes its hydration and hence permeability to ions.