Fig. 6: Proposed molecular mechanism of PA block of TRPV channels.
From: Molecular basis of TRPV3 channel blockade by intracellular polyamines
A Modified kinetic model of TRPV3 inhibition by intracellular PAs. The model assumes that spermine interaction blocks the open channel. TRPV3-bound PA may either return to the cytoplasm, or permeate the channel and exit to the extracellular side, or force the channel to close. All transitions are reversible, however extracellular PA concentration is assumed to be zero. Relative conductance (Grel, Function 2) is a function of intracellular PA and eight parameters (constants ka1, ka-1, ka2, KC, and apparent charges associated with them), where KC = kb1 / kb-1 and represents an equilibrium binding constant of PA bound to the closed TRPV channel. B Schematic representation of the hypothesized molecular mechanism of TRPV channel block by spermine. Key acidic residues (D641 above the SF and E679/E682 below the HBC) are labeled in red, spermine is presented as blue rods, and potassium ions are presented as blue beads. Open TRPV3 in the absence of spermine with both SF and HBC wide open, is permeable to potassium ions. Intracellular spermine (or NASPM) interacts with E679/E682 and blocks permeation. Spermine unblock can occur by return to the cytoplasm or by permeation to the outside. While interacting, spermine promotes channel closure. Model prediction of experimental data for WT and mutant TRPV3 in the presence of 100 µM intracellular spermine (C, n = 6 for WT, n = 5 for all mutants, ± SE) or NASPM (D, n = 5 for all, ± SE), data points from Figs. 2 and 3. Parameters were constrained as noted in Table 3. Data points labeled as empty circles (K169A/E679Q/E682Q) were excluded from analysis.
