Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain

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The molecular basis of the thermal sensitivity of temperature-sensitive channels appears to arise from a specific protein domain rather than integration of global thermal effects. Using systematic chimeric analysis, we show that the N-terminal region that connects ankyrin repeats to the first transmembrane segment is crucial for temperature sensing in heat-activated vanilloid receptor channels. Changing this region both transformed temperature-insensitive isoforms into temperature-sensitive channels and significantly perturbed temperature sensing in temperature-sensitive wild-type channels. Swapping other domains such as the transmembrane core, the C terminus, and the rest of the N terminus had little effect on the steepness of temperature dependence. Our results support that thermal transient receptor potential channels contain modular thermal sensors that confer the unprecedentedly strong temperature dependence to these channels. chimera | temperature gating | temperature jump | thermosensation | pain T he ability to sense temperature is vital to living organisms. In mammals, the neural input on ambient temperature results from specialized groups of neurons that project to the skin. The transducers involve ion channels known as transient receptor potential (TRP) channels (1, 2), which constitute an array of biological thermometers responsive over a broad temperature gradient from noxious cold to noxious hot (3).The molecular mechanism by which temperature changes induce channel opening is not yet known, but the phenomenological tools to analyze the system are known from classical thermodynamic theory. The probability of channel opening follows a Boltzmann relationship to temperature. The enthalpy change (ΔH) between closed and open determines the slope sensitivity of the curve, whereas the entropy change (ΔS) affects its midpoint (T 1∕2 ). The term "threshold" is also commonly used in studies of temperature-sensitive channels to represent the change in temperature required for the response to be larger than the noise level of the recording. Changes in threshold could occur by changes in ∆H or T 1∕2 or the recording noise level.Thermodynamic analyses reveal that thermal TRP channels undergo large enthalpy changes, which accounts for their high temperature sensitivity (4-8). The opening of TRPV1, for example, involves an activation enthalpy of approximately 100 kcal/mol (7), five times the enthalpy change for ligand-or voltage-dependent gating [Q 10 ∼ 2-3 (ref. 9), equivalent to an enthalpy of approximately 20 kcal/mol]. If the free energy change were determined by enthalpy alone, the rate of gating would be very slow because the barrier would be too high. However, thermal TRP channels have evolved to have tightly coupled enthalpy and entropy changes so that the free energy change is relatively small (7). The threshold of activation summarizes the influence of all the temperature-insensitive processes that can regulate gating including the membrane potential (5, 6, 10) and any other allosteric sources such as li...

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confidence: 68%

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confidence: 99%

Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels

Yao

Liu

Feng

2011

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204

“…For example, swapping C-terminal domains between rat TRPV1 and TRPM8 channels has been reported to switch heat and cold sensitivity (27,28). Deletions within the TRPV1 C terminus have been shown to alter thermal threshold (29), and substitutions or point mutations within the turret or outer pore domain of TRPV1 have been shown to alter heat sensitivity (30,31). Recently, the linker region of TRPV1 connecting the pore-forming transmembrane core to the AR-containing N terminus has been suggested to specify heat sensitivity of the channel (32).…”

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confidence: 99%

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

Cordero-Morales¹,

Gracheva²,

Julius

2011

195

188

Transient receptor potential (TRP) channels are polymodal signal detectors that respond to a wide array of physical and chemical stimuli, making them important components of sensory systems in both vertebrate and invertebrate organisms. Mammalian TRPA1 channels are activated by chemically reactive irritants, whereas snake and Drosophila TRPA1 orthologs are preferentially activated by heat. By comparing human and rattlesnake TRPA1 channels, we have identified two portable heat-sensitive modules within the ankyrin repeat-rich aminoterminal cytoplasmic domain of the snake ortholog. Chimeric channel studies further demonstrate that sensitivity to chemical stimuli and modulation by intracellular calcium also localize to the N-terminal ankyrin repeat-rich domain, identifying this region as an integrator of diverse physiological signals that regulate sensory neuron excitability. These findings provide a framework for understanding how restricted changes in TRPA1 sequence account for evolution of physiologically diverse channels, also identifying portable modules that specify thermosensitivity.chemosensation | pain | thermosensation | calcium modulation | somatosensation P rimary afferent (somatosensory) neurons detect a range of physical and chemical stimuli, including temperature, pressure, and noxious irritants (1). The transient receptor potential (TRP) channel family has been shown to play a predominant role in these processes, particularly in regard to thermosensitivity and chemosensitivity (2-5). TRPA1, otherwise known as the "wasabi receptor," plays a key role in somatosensation in evolutionarily diverse phyla, including vertebrate and invertebrate species. Mammalian TRPA1 is expressed by primary afferent sensory neurons of the pain pathway, where it functions as a sensor of environmental and endogenous chemical irritants, such as allyl isothiocyanate (AITC), acrolein, and 4-hydroxynonena, and contributes to cellular mechanisms underlying inflammatory pain (6-9).TRPA1 channels show species-specific functional variation to suit their physiological roles. For example, snakes are unique among vertebrates in that their TRPA1 channels are heat-sensitive, which some species (rattlesnakes, boas, and pythons) have exploited to detect infrared radiation (10). Similarly, insect TRPA1 channels are heat-sensitive and contribute to thermal avoidance behaviors (11)(12)(13)(14). In these cases, however, thermosensitivity comes at the expense of chemosensitivity, such that AITC and other chemical irritants still activate these channels but with reduced potency compared with mammalian orthologs (10). Despite clear physiological differences between snake and mammalian TRPA1 channels, they share significant amino acid identity (56%), providing a unique opportunity to exploit sequence comparisons and domain swaps to pinpoint structural elements associated with stimulus detection and/or gating. Delineating elements that contribute to TRPA1 function will provide insights into the evolutionary process whereby structural changes lead t...

“…Studies in TRPV1 showed that heat sensitivity can be altered by mutations in virtually any channel domain (33,(40)(41)(42)(43)(44)(45)(46), supporting the idea that molecular determinants of the hypothetical heat-sensing module are not localized in a single topologically defined channel element, but are instead distributed throughout the molecule (35). Although a full-length structure of TRPV1 is currently unavailable, the recent cryo-EM structure of TRPA1 revealed tight interations between the N-and C-termini (47), suggesting that topologically distant domains could be functionally coupled, in which case mutations that affect heat sensing or coupling mechanisms could be functionally indistinguishable.…”

Section: Discussionmentioning

confidence: 99%

Low-cost functional plasticity of TRPV1 supports heat tolerance in squirrels and camels

Laursen

Schneider

Merriman

et al. 2016

The ability to sense heat is crucial for survival. Increased heat tolerance may prove beneficial by conferring the ability to inhabit otherwise prohibitive ecological niches. This phenomenon is widespread and is found in both large and small animals. For example, ground squirrels and camels can tolerate temperatures more than 40°C better than many other mammalian species, yet a molecular mechanism subserving this ability is unclear. Transient receptor potential vanilloid 1 (TRPV1) is a polymodal ion channel involved in the detection of noxious thermal and chemical stimuli by primary afferents of the somatosensory system. Here, we show that thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and Bactrian camels (Camelus ferus) express TRPV1 orthologs with dramatically reduced temperature sensitivity. The loss of sensitivity is restricted to temperature and does not affect capsaicin or acid responses, thereby maintaining a role for TRPV1 as a detector of noxious chemical cues. We show that heat sensitivity can be reengineered in both TRPV1 orthologs by a single amino acid substitution in the N-terminal ankyrin-repeat domain. Conversely, reciprocal mutations suppress heat sensitivity of rat TRPV1, supporting functional conservation of the residues. Our studies suggest that squirrels and camels co-opt a common molecular strategy to adapt to hot environments by suppressing the efficiency of TRPV1-mediated heat detection at the level of somatosensory neurons. Such adaptation is possible because of the remarkable functional flexibility of the TRPV1 molecule, which can undergo profound tuning at the minimal cost of a single amino acid change.TRPV1 | thermosensation | thirteen-lined ground squirrel | bactrian camel | sensory physiology T he somatosensory system allows animals to distinguish between innocuous and noxious temperatures, guiding them to environments most amenable for life and reproduction. In general, mammals avoid contacting surfaces heated more than 40°C, which helps stave off the danger of tissue damage, but at the same time limits inhabitable areas. Mammalian extremophiles such as camels and diurnal rodents, including ground squirrels and chipmunks (Fig. 1A), thrive under thermal conditions that are harmful or even fatal to other animals. The mechanism(s) that allows such species to cope with high temperatures are complex and involve various organs and tissues, including thermoregulatory and somatosensory systems (1-5), but the exact molecular adaptations remain enigmatic.In rodents, noxious stimuli, including temperature, are detected in the skin by the terminal endings of C-type nociceptors from dorsal root or trigeminal ganglia marked by the expression of the heat-activated ion channel transient receptor potential vanilloid 1 (TRPV1) (6-9). Deletion of Trpv1 in mice does not abolish pain sensitivity in general (10) but diminishes sensitivity to noxious temperatures more than 50°C (7,8). Whereas the general pathways of heat sensitivity in standard laboratory rodents has been worked out in some...