The molecular sensors that mediate temperature changes in living organisms are a large family of proteins known as thermosensitive transient receptor potential (TRP) ion channels. These membrane proteins are polymodal receptors that can be activated by cold or hot temperatures, depending on the channel subtype, voltage, and ligands. The stimuli sensors are allosterically coupled to a pore domain, increasing the probability of finding the channel in its ion conductive conformation. In this review we first discuss the allosteric coupling between the temperature and voltage sensor modules and the pore domain, and then discuss the thermodynamic foundations of thermo-TRP channel activation. We provide a structural overview of the molecular determinants of temperature sensing. We also posit an anisotropic thermal diffusion model that may explain the large temperature sensitivity of TRP channels. Additionally, we examine the effect of several ligands on TRP channel function and the evidence regarding their mechanisms of action.

Ion channels are membrane proteins that mediate efficient ion transport across the hydrophobic core of cell membranes, an unlikely process in their absence. K⁺ channels discriminate K⁺ over cations with similar radii with extraordinary selectivity and display a wide diversity of ion transport rates, covering differences of two orders of magnitude in unitary conductance. The pore domains of large- and small-conductance K⁺ channels share a general architectural design comprising a conserved narrow selectivity filter, which forms intimate interactions with permeant ions, flanked by two wider vestibules toward the internal and external openings. In large-conductance K⁺ channels, the inner vestibule is wide, whereas in small-conductance channels it is narrow. Here we raise the idea that the physical dimensions of the hydrophobic internal vestibule limit ion transport in K⁺ channels, accounting for their diversity in unitary conductance.

In mammals, temperature-sensitive TRP channels make membrane conductance of cells extremely temperature dependent, allowing the detection of temperature ranging from noxious cold to noxious heat. We progressively deleted the distal carboxyl terminus domain (CTD) of the cold-activated melastatin receptor channel, TRPM8. We found that the enthalpy change associated with channel gating is proportional to the length of the CTD. Deletion of the last 36 amino acids of the CTD transforms TRPM8 into a reduced temperature-sensitivity channel (Q₁₀ ∼4). Exposing the intracellular domain to a denaturing agent increases the energy required to open the channel indicating that cold drives channel gating by stabilizing the folded state of the CTD. Experiments in the presence of an osmoticant agent suggest that channel gating involves a change in solute-inaccessible volume in the CTD of ∼1,900 ų. This volume matches the void space inside the coiled coil according to the cryogenic electron microscopy structure of TRPM8. The results indicate that a folding–unfolding reaction of a specialized temperature-sensitive structure is coupled to TRPM8 gating. Significance Sensory and homeostatic responses in several organisms depend on the exquisite temperature dependence of ion channels of the transient receptor potential family (thermo-TRP). To date, this temperature dependence has been explained either in terms of the existence of a dedicated temperature sensor or by the increase in the molar heat capacity during channel gating. We found that the Carboxy Terminus Domain (CTD) is required for temperature-driven gating of the cold-activated TRPM8 channel and that this domain folds in response to cold. Here we propose that the CTD of the TRPM8 channel is a bona fide temperature sensor that drives channel gating due to an increase in the molar heat capacity during the folded-to-unfolded transition.

Living organisms require detecting the environmental thermal clues for survival, allowing them to avoid noxious stimuli or find prey moving in the dark. In mammals, the Transient Receptor Potential ion channels superfamily is constituted by 27 polymodal receptors whose activity is controlled by small ligands, peptide toxins, protons and voltage. The thermoTRP channels subgroup exhibits unparalleled temperature dependence -behaving as heat and cold sensors. Functional studies have dissected their biophysical features in detail, and the advances of single-particle Cryogenic Electron microscopy provided the structural framework required to propose detailed channel gating mechanisms. However, merging structural and functional evidence for temperature-driven gating of thermoTRP channels has been a hard nut to crack, remaining an open question nowadays. Here we revisit the highlights on the study of heat and cold sensing in thermoTRP channels in the light of the structural data that has emerged during recent years.

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is a polymodal receptor that mediates the flux of cations across the membrane in response to several stimulus including heat, voltage and several ligands. The best known agonist of TRPV1 channels is capsaicin, the pungent component of "hot chilli peppers". Additionally, peptides obtained from the venom of poisonous animals binds to TRPV1 with high affinity to modulate channel gating. TRPV1 channels gating is also modulated by lipids such as PIP2, Lysophosphatidic acid and cholesterol. Here, we discuss the functional evidence regarding ligand-dependent activation of TRPV1 channels in the light of the structural data recently obtained by cryo-electron microscopy. Mechanistic insights on coupling between ligand binding and allosteric gating of TRPV1 channels and the relevance of an accurate biophysical characterization of polymodal receptors for drug design in novel pain therapies are also the focus of this review.

Significance: The neuronal action potential is a self-propagating transient depolarization traveling along the neuron membrane. This signal is produced by the coordinated activation of voltage-gated ion channels (VGCs), a family of ion-selective transmembrane proteins activated by depolarization. Sodium and calcium VGCs reinforce the signal, while potassium VGCs terminate it. A conserved voltage sensor domain (VSD) in VGCs responds with an unresolved conformational change driven by the transmembrane electrophoretic displacements of four arginine side chains. We show that those arginine side chains are stabilized by water impregnating the VSD and that, upon activation, displace large and dissimilar aqueous volumes at both protein faces. This charge translocation entails a transporter-like remodeling of water–protein interfaces that should create mechanical spikes accompanying action potentials.