Veit Flockerzi

The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels.

The mammalian sensory system is capable of discriminating thermal stimuli ranging from noxious cold to noxious heat. Principal temperature sensors belong to the TRP cation channel family, but the mechanisms underlying the marked temperature sensitivity of opening and closing (‘gating’) of these channels are unknown. Here we show that temperature sensing is tightly linked to voltage-dependent gating in the cold-sensitive channel TRPM8 and the heat-sensitive channel TRPV1. Both channels are activated upon depolarization, and changes in temperature result in graded shifts of their voltage-dependent activation curves. The chemical agonists menthol (TRPM8) and capsaicin (TRPV1) function as gating modifiers, shifting activation curves towards physiological membrane potentials. Kinetic analysis of gating at different temperatures indicates that temperature sensitivity in TRPM8 and TRPV1 arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. Our results suggest a simple unifying principle that explains both cold and heat sensitivity in TRP channels.

Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4

Mast cells are key effector cells in allergic reactions. Aggregation of the receptor FcεRI in mast cells triggers the influx of calcium (Ca2+) and the release of inflammatory mediators. Here we show that transient receptor potential TRPM4 proteins acted as calcium-activated nonselective cation channels and critically determined the driving force for Ca2+ influx in mast cells. Trpm4−/− bone marrow–derived mast cells had more Ca2+ entry than did TRPM4+/+ cells after FcεRI stimulation. Consequently, Trpm4−/− bone marrow–derived mast cells had augmented degranulation and released more histamine, leukotrienes and tumor necrosis factor. Trpm4−/− mice had a more severe IgE-mediated acute passive cutaneous anaphylactic response, whereas late-phase passive cutaneous anaphylaxis was not affected. Our results establish the physiological function of TRPM4 channels as critical regulators of Ca2+ entry in mast cells.

Mammalian transient receptor potential (TRP) cation channels

TRPs -Truly Remarkable Proteins.- The TRCP Subfamily: TRPC1.- TRPC2.- TRPC3- a Multifunctional Signaling Molecule.- TRPC4 and TRPC4-Containing Channels.- TRPC5.- TRPC6: Physiological Function and Pathophysiological Relevance.- Transient Receptor Potential Canonical 7 (TRPC7).- The TRPV Subfamily: TRPV1.- TRPV2.- TRPV3.- The TRPV4 Channel.- TRPV5, a Ca2+ Channel for the Fine Tuning of Ca2+ Reabsorption.- TRPV6 Channels.- The TRPM Subfamily: TRPM1.- TRPM2.- TRPM3.-TRPM4.- TRPM5.- TRPM6.- TRPM7.- TRPM8.- The TRPA1, TRPML and TRPP Subfamily: TRPA1.- TRPML1: An Ion Channel in the Lysosome.- TRPML2 and Mucolipin Evolution.- TRPML3.- TRPP Subfamily and Polycystin-1 Proteins.