Thermal Gating of TRP Ion Channels: Food for ... - Semantic Scholar

PERSPECTIVE

Thermal Gating of TRP Ion Channels: Food for Thought? Emily R. Liman* (Published 14 March 2006)

www.stke.org/cgi/content/full/sigtrans;2006/326/pe12

Cold-activated

Po

Po

Heat-activated

are also thermo-sensitive, including TRPV2, TRPV3, and possiThe ability to detect temperatures is a fundamental process that bly TRPA1, and together they cover the entire range of temperaallows animals to select appropriate environmental conditions tures over which mammals are sensitive (6). in order to maintain optimal functioning. Perhaps as a by-product of this ability, we humans The identif ication of TRP use temperature for a more aeschannels as the molecular baNa+ thetic function—preparing and sis for thermosensation has choosing foods. We strongly raised a new mystery that has Out + prefer our coffee hot and our since intrigued channel phys+ soda cold, but why? Although a iologists. Basic principles of + + large part of temperature’s efchemistry tell us that reacIn fect on taste can be attributed to tions proceed faster at higher Closed Open the increased volatility of foods temperatures, and thus we enhancing our sense of smell, tend to think that ion chanthere also appears to be an innels, like other proteins, will teraction between temperature work more effectively at V ViT and taste receptors on the warm temperatures. So how O O C C tongue. Previous work has is it that an ion channel, such V ViT shown that warm temperatures as TRPM8, can be opened increase our perception of by cold temperatures? This sweetness (1–3) [but see (4)], question was elegantly addressed by the Nilius group and Nilius and collaborators ( T) in 2004 in a paper that prosuggest that this effect is at posed a theoretical frameleast in part mediated by the ion ( T) work for understanding thermochannel TRPM5 (5). gating of TRP channels (10). The sensation of temperature Vm Vm in humans and other vertebrates They noticed that all thermois primarily, if not solely, mediTRPs have in common a V V weak sensitivity to membrane ated by members of the tranvoltage. That is, after activasient receptor potential (TRP) family of ion channels (6). The Fig. 1. Model for thermal gating of TRP channels. In this simple tion by appropriate stimuli, first thermosensitive TRP chan- model, the channel can occupy one of two states—closed and both TRPM8 and TRPV1 are nel was identified by expression open—and transitions between the two states are sensitive to more readily activated at poscloning, using sensitivity to the voltage (depolarization promotes entry into the open state). itive voltages than at negative vanilloid capsaicin, the key Thermosensitivity of the channel results from an asymmetry in voltages. This voltage sensicomponent of hot chili peppers, the temperature dependence of opening and closing transitions. tivity manifests itself in outas the stimulus (7). TRPV1 (for For the heat-activated channels, the opening transition is more ward rectification of the curvanilloid), as this channel was temperature sensitive, whereas for cold-activated channels, the rents (enhanced outward as subsequently named, by itself closing transition is more temperature sensitive. This model pre- compared to inward current) constitutes a temperature- and dicts that the probability that channels are open (Po) as a func- when the membrane potential tion of voltage (V) shifts to the left upon warming for TRPV1 and capsaicin-sensitive ion channel, is steadily increased. At first to the right for TRPM8, a prediction that is validated by the data thus providing a biological ex- [based on (10, 11)]. See (12) for an alternate allosteric model glance the voltage sensitivity planation for why chili peppers for thermo-gating of TRPM8. of TRP channels seems countaste hot. Moreover, it also proterintuitive—the channels are vides a tool for understanding the encoding of thermal informaleast likely to open precisely over the voltage range of a resting tion in the peripheral nervous system. A similar strategy was cell. But the data from Nilius’s group in fact provides a simple used to identify TRPM8, an ion channel activated by cold (temteleological explanation for this observation. They propose that perature below 28°C) and menthol (8, 9). Other TRP channels temperature acts to shift the voltage sensitivity of the thermoTRP channels, and that this underlies their thermosensitivity (10, 11). Department of Biological Sciences and Program in Neuroscience, University of Southern California, 3641 Watt Way, Los Angeles, CA To understand how temperature might act on the thermo90089, USA . TRP channels, consider the simplest possible model for their gating (10, 11) (Fig. 1). In this model there are just two states: *Contact information. E-mail, [email protected]

Page 1

PERSPECTIVE closed and open. Transitions between these two states are sensitive to voltage, such that increasing voltage enhances the probability that the channel will be in the open state. Opening and closing rates are also temperature sensitive, increasing at higher temperatures. Suppose that in the case of one channel (TRPV1), the opening rate is highly temperature sensitive, whereas the closing rate is relatively insensitive to temperature. In this scenario, increasing temperature will act to open the channel and will at the same time shift the midpoint for voltage activation of the channel to the left. Conversely, if the closing rate of the channel is much more temperature sensitive than the opening rate, warmer temperature will speed closing of the channel and the channel will be cold-activated. This model appears to be consistent, generally, with the kinetics of TRPV1 and TRPM8 (10, 11), suggesting that it represents real physical properties of the proteins. It should be noted that an alternative model proposed by Latorre and colleagues instead suggests that thermo-gating of TRPs involves an allosteric interaction between the voltage gating of the channels, which is not inherently temperature sensitive, and a separate conformation change, which is highly temperature sensitive (12). If temperature acts on the voltage-dependent gating of TRPV1 and TRPM8, one is led to wonder whether other weakly voltage-dependent channels, TRP or otherwise, might also be thermosensitive. TRPM4 and TRPM5 show voltage-dependent gating similar to that of TRPV1 and TRPM8, yet these channels have as their primary stimulus Ca 2+, which gates them at micromolar concentrations (13–17). TRPM5 is involved in taste sensory transduction (18, 19), whereas TRPM4 plays a role in regulating Ca2+ signaling in T lymphocytes (20). Thus, it is perhaps surprising that both channels are highly temperature sensitive, like their thermo-TRP channel relatives (5). Moreover, even though they share more structural similarity to TRPM8 than to TRPV1, activation of both channels is enhanced at warm temperatures. Consistent with the model proposed for thermosensitivity of TRPV1, the opening rates of TRPM4 and TRPM5 are more temperature sensitive than the closing rates (5). So the unified model for thermosensitivity of TRP channels has now been extended to two more TRP channels previously unrecognized to have thermosensitivity, giving us confidence that the model is a good approximation of reality. But again, a new mystery is revealed and one is left to wonder why opening of one channel while closing of another is temperature sensitive. Only an understanding at the structural level, which many groups have set their sights on, will solve this mystery. In the meantime, the gustatory crowd will want to know what the thermosensitivity of TRPM5 means for taste. TRPM5 was identified as an abundant component of taste cells by the Margolskee group (18) and was later shown to be essential for sweet, bitter, and amino acid (umami) tastes by the Zuker and Ryba groups (19). Bitter, sweet, and umami tastes are mediated by G protein–coupled receptors that signal through the phospholipase C pathway (19). It is likely that the TRPM5 channel is activated downstream of this pathway and is the transduction channel for these tastes, although this remains to be shown (Fig. 2). To determine whether temperature sensitivity of TRPM5 has relevance for taste, Talevera et al. (5) asked whether sweet taste is sensitive to temperature and showed this to be so. Nerve responses in mice to sweet substances are severely diminished at low temperatures, consistent with results from human psychophysics. This reduction in activity

could be attributed to effects on the taste receptors, the second messenger signaling pathway, or on TRPM5. A clear answer as to whether TRPM5 is indeed the culprit will await the creation of a temperature-insensitive form of the channel that can be knocked into mice. Whether such a channel, in which temperature sensitivity of opening and closing is completely balanced, can in fact be generated is itself a fascinating question that will be answered only after structural mechanisms of thermo-gating are better understood. In the meantime, the Nilius group has given us much food for thought.

Sweet

+

Sweeter

Fig. 2. Signaling of sweet taste is enhanced at warm temperatures. The frequency of action potentials in gustatory nerves in response to sweet chemicals is increased at warmer temperatures. TRPM5 channels are essential for sweet taste, and it is hypothesized that the increased activity of TRPM5 channels at warm temperatures underlies thermal sensitivity of sweet taste (5). References and Notes 1. D. H. McBurney, V. B. Collings, L. M. Glanz, Temperature dependence of human taste responses. Physiol. Behav. 11, 89–94 (1973). 2. L. M. Bartoshuk, K. Rennert, J. Rodin, J. C. Stevens, Effects of temperature on the perceived sweetness of sucrose. Physiol. Behav. 28, 905–910 (1982). 3. A. Cruz, B. G. Green, Thermal stimulation of taste. Nature 403, 889–892 (2000). 4. S. S. Schiffman, E. A. Sattely-Miller, B. G. Graham, J. L. Bennett, B. J. Booth, N. Desai, I. Bishay, Effect of temperature, pH, and ions on sweet taste. Physiol. Behav. 68, 469–481 (2000). 5. K. Talavera, K. Yasumatsu, T. Voets, G. Droogmans, N. Shigemura, Y. Ninomiya, R. F. Margolskee, B. Nilius, Heat activation of TRPM5 underlies thermal sensitivity of sweet taste. Nature 438, 1022–1025 (2005). 6. S. E. Jordt, D. D. McKemy, D. Julius, Lessons from peppers and peppermint: The molecular logic of thermosensation. Curr. Opin. Neurobiol. 13, 487–492 (2003). 7. M. J. Caterina, M. A. Schumacher, M. Tominaga, T. A. Rosen, J. D. Levine, D. Julius, The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997). 8. D. D. McKemy, W. M. Neuhausser, D. Julius, Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002). 9. A. M. Peier, A. Moqrich, A. C. Hergarden, A. J. Reeve, D. A. Andersson, G. M. Story, T. J. Earley, I. Dragoni, P. McIntyre, S. Bevan, A. Patapoutian, A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002).


Page 2

PERSPECTIVE 10. T. Voets, G. Droogmans, U. Wissenbach, A. Janssens, V. Flockerzi, B. Nilius, The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430, 748–754 (2004). 11. B. Nilius, K. Talavera, G. Owsianik, J. Prenen, G. Droogmans, T. Voets, Gating of TRP channels: A voltage connection? J. Physiol. 567, 35–44 (2005). 12. S. Brauchi, P. Orio, R. Latorre, Clues to understanding cold sensation: Thermodynamics and electrophysiological analysis of the cold receptor TRPM8. Proc. Natl. Acad. Sci. U.S.A. 101, 15494–15499 (2004). 13. P. Launay, A. Fleig, A. L. Perraud, A. M. Scharenberg, R. Penner, J. P. Kinet, TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell 109, 397–407 (2002). 14. T. Hofmann, V. Chubanov, T. Gudermann, C. Montell, TRPM5 is a voltagemodulated and Ca(2+)-activated monovalent selective cation channel. Curr. Biol. 13, 1153–1158 (2003). 15. D. Liu, E. R. Liman, Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5. Proc. Natl. Acad. Sci. U.S.A. 100, 15160–15165 (2003). 16. B. Nilius, J. Prenen, G. Droogmans, T. Voets, R. Vennekens, M. Freichel, U. Wissenbach, V. Flockerzi, Voltage dependence of the Ca2+-activated cation channel TRPM4. J. Biol. Chem. 278, 30813–30820 (2003).

17. D. Prawitt, M. K. Monteilh-Zoller, L. Brixel, C. Spangenberg, B. Zabel, A. Fleig, R. Penner, TRPM5 is a transient Ca2+-activated cation channel responding to rapid changes in [Ca2+]i. Proc. Natl. Acad. Sci. U.S.A. 100, 15166–15171 (2003). 18. C. A. Perez, L. Huang, M. Rong, J. A. Kozak, A. K. Preuss, H. Zhang, M. Max, R. F. Margolskee, A transient receptor potential channel expressed in taste receptor cells. Nat. Neurosci. 5, 1169–1176 (2002). 19. Y. Zhang, M. A. Hoon, J. Chandrashekar, K. L. Mueller, B. Cook, D. Wu, C. S. Zuker, N. J. Ryba, Coding of sweet, bitter, and umami tastes: Different receptor cells sharing similar signaling pathways. Cell 112, 293–301 (2003). 20. P. Launay, H. Cheng, S. Srivatsan, R. Penner, A. Fleig, J. P. Kinet, TRPM4 regulates calcium oscillations after T cell activation. Science 306, 1374–1377 (2004). 21. I thank D. McKemy and D. Arnold for helpful discussion and comments on the manuscript. Supported by a grant from the NIH (K02DC05000).

Citation: E. R. Liman, Thermal gating of TRP ion channels: Food for thought? Sci. STKE 2006, pe12 (2006).


Page 3