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

Abstract

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.Mammals sense ambient temperature through primary afferent sensory neurons of the dorsal root and trigeminal ganglia 1,2 . These cells convey thermal information from peripheral tissues to the spinal cord and brain, where the signals are integrated and interpreted, resulting in appropriate reflexive and cognitive responses. The mammalian sensory system is capable of detecting and discriminating thermal stimuli over a broad temperature spectrum, ranging from noxious cold (,8 8C) to noxious heat (.52 8C), which implies the existence of different types of temperature sensors with distinct thermal sensitivities 2 . Accumulated evidence suggests that the principal temperature sensors in the sensory nerve endings of mammals belong to the transient receptor potential (TRP) superfamily of cation channels 3,4 . At present, six temperature-sensitive TRP channels (or thermoTRPs) 2 have been described, that together cover almost the entire range of temperatures that mammals are able to sense. Four TRP channels belonging to the TRPV subfamily are activated by heating, with characteristic activation temperatures ranging from warm temperatures (.25 8C for TRPV4; .31 8C for TRPV3) 5-9 to heat (.43 8C for TRPV1) 10 and noxious heat (.52 8C for TRPV2) 11 . TRPM8 and TRPA1 (ANKTM1) are activated by cooling, (,28 8C for TRPM8; ,18 8C for TRPA1) [12][13][14] ; although the cold-sensitivity of TRPA1 has been disputed 15 . The origin of the remarkably steep temperature sensitivity of the thermoTRPs is still obscure. Until now, three possible mechanisms for temperature-dependent channel gating have been envisaged 3 . Changes in temperature could lead to the production and binding of channel-activating ligands. Alternatively, the channel protein may undergo temperature-dependent structural rearrangements leading to channel opening. Finally, thermoTRPs may be able to sense changes in membrane tension due to temperature-dependent lipid bilayer...

The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degeneration

“…5a). Thus, the outward rectification of TRPML3, like that of other TRP channels (13)(14)(15)(16), is probably due to a voltage-sensitive increase in open probability (Fig. 4b).…”

“…4b and 5b). The outward rectification characteristic of many TRP channels, including wild-type TRPML3, results from a weak voltage sensitivity: Open probability increases with ''depolarization'' at positive membrane potentials, in the nonphysiological range (13)(14)(15)(16) (Fig. 4b).…”

Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes

“…Thus, TRPM2, TRPM3 and TRPM8 are Ca 2+ permeable nonselective cation channels, which differ substantially with respect to their activation stimuli (Chuang et al 2004;Grimm et al 2003;Hara et al 2002;Lee et al 2003;McKemy et al 2002;Peier et al 2002;Sano et al 2001;Wehage et al 2002). TRPM8 is activated by low temperature (Chuang et al 2004;Voets et al 2004a), while TRPM2 is stimulated by intracellular ADP-ribose, NAD + and oxidative stress (Hara et al 2002;Perraud et al 2001Perraud et al , 2003). TRPM3 appears to be activated by hypoosmotic cell swelling, rises of intracellular Ca 2+ and by D-erythro-sphingosine (Grimm et al 2003(Grimm et al , 2004Lee et al 2003).…”

TRP Channels and Pruritus

“…TRPV1 was shown to be modulated by the protein kinase C (PKC) [183,[194][195][196], phospholipase C (PLC), and phosphatidylinositol 4,5-bisphosphate (PIP 2 ) [184,[197][198][199][200] systems as well as by intracellular ATP [201]. The sensitization process eventually results in the shift of the activation temperature and voltage threshold towards more physiological ranges [195,[202][203][204].…”