Unlike the gated pore model, which assumes the existence of a movable gate within the molecule, the gateless gating model (H. R. Leuchtag, Voltage-Sensitive Ion Channels, Springer 2008) (VSIC) explains ion-channel gating as a phase transition. Under this model, the closed channel conformation imposed by the resting electric field is a compact, ordered phase with behavior, such as critical temperature, hysteresis, fractional dispersion exponent (constant phase angle) and Curie-Weiss law, similar to that of phases seen in ferroelectric liquid crystals (VSIC, pp. 355-383). In the absence of a toxin molecule, threshold membrane depolarization indirectly brings about a stochastic phase transition to a less ordered phase in which S4 segments expand by the mutual repulsion of their positively charged residues. The resulting wider pitch of permeation pathway α helices elastically linked to the S4s permits ion replacement in the interloop H bonds and the subsequent percolation of permeant ions through the channel (VSIC, 477f, 506f). With an externally applied tetrodotoxin (TTX) or analog molecule complexed in the channel, however, the ordered phase is pinned by the toxin, inhibiting the transition to the ion-conducting phase (VSIC, 76, 382f). Phase pinning by impurities is an established effect in ferroelectric liquid crystals. In the toxin, a guanidinium group, H2N+=C(NH2)2, a highly resonant, planar, positive ion, is active in pinning the closed phase. The fact that guanidinium is also found in ferroelectric crystals such as guanidinium aluminum sulfate hexahydrate suggests that TTX enhances the spontaneous polarization of the resting phase. This explanation by the gateless gating model of specific toxin action is based on physical principles; in contrast, the phrase “TTX blocks the pore” offered by the gated pore model is vague and at the macroscopic rather than molecular scale.
Search from 250 M+ research papersSearch from 250 M+ research papers
Feb 1, 2024
Nilesh Pote + 3
Open Access