Ion Transport from Physics to Physiology: the Missing Rungs in the Ladder
Looking for the mechanisms of temperature activation in TRPV1 ion channels.León Islas
TRPV1 is the prototypical thermal-activated ion channel. Although great strides have been made in our understanding of the gating mechanisms of these channels, the molecular events that give rise to its very high heat sensitivity remain elusive. We know that the process of opening by heat absorption is characterized by a very large enthalpy and entropy change, in the order of the changes that are observed during thermal denaturation of soluble proteins. We have studied the heat activation of TRPV1 channels by a fast activation method and characterized a temperature-dependent inactivation process that happens in the absence of Ca2+ ion. This heat-dependent process is coupled to the heat-dependent opening step and is completely irreversible. Importantly, inactivation is accompanied by reductions in the heat sensitivity of channel gating. The N-terminal region of TRPV1 has been previously implicated in heat-dependent gating. Biochemical characterization of the ankyrin repeat domains isolated from the N-terminus revealed a thermal denaturation that is irreversible and occurs in the same range of temperatures for opening and inactivation. Our data suggest that perhaps opening and inactivation in TRPV1 are at least partially mediated by heat absorption at the ankyrin repeats and that this process occurs by partial denaturation of the native protein structure.