Inactivation in TRPV1 Ion Channels

TRPV1 are cation-permeable ion channels involved in several physiological processes. TRPV1 can be activated by several, very different, stimuli. Chief among these is a characteristic activation by temperatures in the noxious range and activation by several ligands, including capsaicin, the pungent compound that gives chilies their characteristic spiciness. Depolarizing voltages can also activate these channels, although with a very small voltage-dependence (the associated valence of activation is at most 1 elementary charge, eo). In the absence of any other ligands, voltage behaves as a “partial agonist”, producing a maximal open probability of less than 0.5 at extremely high voltages. Activation by voltage is more effective when combined with other activation modes, including activating by capsaicin and temperature. It has been previously shown that allosteric coupling models can describe this behavior, with independent voltage, temperature and ligand gating modules allostericaly coupled to a pore module. Here we show that in the presence of these activators, TRPV1 channels show a marked inactivation behavior induced by high voltages, which can be seen as time- and voltage-dependent reductions in the magnitude of the outward currents and can be explained by models with inactivation happening after the open state. High activating temperatures (47-60 oC) can also induce inactivation by itself, even at moderate voltages and this temperature-dependent inactivation seems to be an irreversible process. Inactivation of TRPV1 has not been previously described; although careful inspection of previously published TRPV1 current records show evidence of this phenomenon. This work supported by grants PAPIIT-DGAPA-UNAM No. IN209515 to LDI and No. IN200314 to TR and CONACYT Fronteras de la Ciencia No.77 to LDI and TR.