Perspective

Thermal Gating of TRP Ion Channels: Food for Thought?

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Science's STKE  14 Mar 2006:
Vol. 2006, Issue 326, pp. pe12
DOI: 10.1126/stke.3262006pe12

Abstract

Members of the family of transient receptor potential (TRP) ion channels mediate a wide range of sensory modalities, including thermosensation and taste. Among the "thermo-TRPs," some, such as TRPV1, are activated by warm temperatures, whereas others, such as TRPM8, are activated by cold. How is temperature able to have such strong and opposing effects on these related channels? Although at a structural level the answer to this question is not known, an elegant biophysical model has been proposed that accounts for the different thermosensitivities of TRP channels. This model posits that temperature acts by shifting the inherent weak voltage sensitivity of TRPV1 and TRPM8 in opposite directions, thus promoting opening of TRPV1 at warm temperatures and TRPM8 at cold temperatures. TRPM5, which is distantly related to TRPM8, is a Ca2+-activated cation channel expressed in taste cells that is essential for sweet, bitter, and umami tastes. Like TRPV1 and TRPM8, TRPM5 is weakly sensitive to voltage and thus may also be temperature sensitive. A recent report shows that activity of TRPM5 is increased at warm temperatures, suggesting that heat may enhance the perception of taste through direct modulation of the putative taste transduction channel.

The ability to detect temperatures is a fundamental process that allows animals to select appropriate environmental conditions in order to maintain optimal functioning. Perhaps as a by-product of this ability, we humans use temperature for a more aesthetic function—preparing and choosing foods. We strongly prefer our coffee hot and our soda cold, but why? Although a large part of temperature’s effect on taste can be attributed to the increased volatility of foods enhancing our sense of smell, there also appears to be an interaction between temperature and taste receptors on the tongue. Previous work has shown that warm temperatures increase our perception of sweetness (13) [but see (4)], and Nilius and collaborators suggest that this effect is at least in part mediated by the ion channel TRPM5 (5).

The sensation of temperature in humans and other vertebrates is primarily, if not solely, mediated by members of the transient receptor potential (TRP) family of ion channels (6). The first thermosensitive TRP channel was identified by expression cloning, using sensitivity to the vanilloid capsaicin, the key component of hot chili peppers, as the stimulus (7). TRPV1 (for vanilloid), as this channel was subsequently named, by itself constitutes a temperature- and capsaicin-sensitive ion channel, thus providing a biological explanation for why chili peppers taste hot. Moreover, it also provides a tool for understanding the encoding of thermal information in the peripheral nervous system. A similar strategy was used to identify TRPM8, an ion channel activated by cold (temperature below 28°C) and menthol (8, 9). Other TRP channels are also thermo-sensitive, including TRPV2, TRPV3, and possibly TRPA1, and together they cover the entire range of temperatures over which mammals are sensitive (6).

The identification of TRP channels as the molecular basis for thermosensation has raised a new mystery that has since intrigued channel physiologists. Basic principles of chemistry tell us that reactions proceed faster at higher temperatures, and thus we tend to think that ion channels, like other proteins, will work more effectively at warm temperatures. So how is it that an ion channel, such as TRPM8, can be opened by cold temperatures? This question was elegantly addressed by the Nilius group in 2004 in a paper that proposed a theoretical framework for understanding thermo-gating of TRP channels (10). They noticed that all thermo-TRPs have in common a weak sensitivity to membrane voltage. That is, after activation by appropriate stimuli, both TRPM8 and TRPV1 are more readily activated at positive voltages than at negative voltages. This voltage sensitivity manifests itself in outward rectification of the currents (enhanced outward as compared to inward current) when the membrane potential is steadily increased. At first glance the voltage sensitivity of TRP channels seems counterintuitive—the channels are least likely to open precisely over the voltage range of a resting cell. But the data from Nilius’s group in fact provides a simple teleological explanation for this observation. They propose that temperature acts to shift the voltage sensitivity of the thermo-TRP channels, and that this underlies their thermosensitivity (10, 11).

To understand how temperature might act on the thermo-TRP channels, consider the simplest possible model for their gating (10, 11) (Fig. 1). In this model there are just two states: 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).

Fig. 1.
Fig. 1.

Model for thermal gating of TRP channels. In this simple model, the channel can occupy one of two states—closed and open—and transitions between the two states are sensitive to voltage (depolarization promotes entry into the open state). Thermosensitivity of the channel results from an asymmetry in the temperature dependence of opening and closing transitions. For the heat-activated channels, the opening transition is more temperature sensitive, whereas for cold-activated channels, the closing transition is more temperature sensitive. This model predicts that the probability that channels are open (Po) as a function of voltage (V) shifts to the left upon warming for TRPV1 and to the right for TRPM8, a prediction that is validated by the data [based on (10, 11)]. See (12) for an alternate allosteric model for thermo-gating of TRPM8.

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 Ca2+, which gates them at micromolar concentrations (1317). 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.

Fig. 2.
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).

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