The molecular and cellular basis of thermosensation in mammals

Palkar, Radhika; Lippoldt, Erika K.; McKemy, David D.

doi:10.1016/j.conb.2015.01.010

Cited by 67 publications

(69 citation statements)

References 50 publications

(60 reference statements)

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“…What is a remarkable and seminal result of our study is that injury-induced cold allodynia of multiple etiologies is totally dependent on GFRα3, unlike the redundant nature of heat and mechanical pain that signal through a diverse repertoire of cell surface receptors (1). NGF, protons, bradykinin, and histamine, to name a few, are all capable of potentiating TRPV1 responses (7,29,44,45) and responsible for the development of heat hyperalgesia. However, only artemin and NGF induce cold allodynia in a manner similar to that found after injury (8).…”

Section: Discussionmentioning

confidence: 99%

“…However, these studies involved either genetically induced artemin overexpression in the periphery (27) or multiple plantar injections of exogenous artemin (28), making it unclear if artemin-GFRα3 signaling influences afferent expression phenotypes under physiological conditions. Thus, to determine if the lack of a cold allodynic phenotype in Gfrα3 −/− mice is a result of alterations in sensory afferent development caused by the absence of GFRα3, we used quantitative PCR to determine expression of array markers involved in cold thermosensation (29). In adult dorsal root ganglia (DRG) (Fig.…”

Section: Significancementioning

confidence: 99%

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Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Lippoldt

Ongun

Kusaka

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tissue injury prompts the release of a number of proalgesic molecules that induce acute and chronic pain by sensitizing pain-sensing neurons (nociceptors) to heat and mechanical stimuli. In contrast, many proalgesics have no effect on cold sensitivity or can inhibit cold-sensitive neurons and diminish cooling-mediated pain relief (analgesia). Nonetheless, cold pain (allodynia) is prevalent in many inflammatory and neuropathic pain settings, with little known of the mechanisms promoting pain vs. those dampening analgesia. Here, we show that cold allodynia induced by inflammation, nerve injury, and chemotherapeutics is abolished in mice lacking the neurotrophic factor receptor glial cell line-derived neurotrophic factor family of receptors-α3 (GFRα3). Furthermore, established cold allodynia is blocked in animals treated with neutralizing antibodies against the GFRα3 ligand, artemin. In contrast, heat and mechanical pain are unchanged, and results show that, in striking contrast to the redundant mechanisms sensitizing other modalities after an insult, cold allodynia is mediated exclusively by a single molecular pathway, suggesting that artemin-GFRα3 signaling can be targeted to selectively treat cold pain.W hen pain continues past its usefulness as a warning of potential tissue damage, it becomes a debilitating condition for which few viable treatments are currently available. The result can be an exacerbation of pain in response to both innocuous (allodynia) and noxious (hyperalgesia) stimuli (1). For example, pain felt with normally pleasant mild cooling (cold allodynia) occurs in many pathological conditions, such as fibromyalgia, multiple sclerosis, stroke, and chemotherapeutic-induced polyneuropathy, but what underlies this specific form of pain at the cellular or molecular level is largely unknown (2-5). Pain-sensing afferent neurons (nociceptors) are sensitized during injury or disease, in part, by a vast array of proalgesic compounds termed the "inflammatory soup" (e.g., neurotrophic factors, protons, bradykinin, prostaglandins, and ATP) (1). These substances are released locally at the site of injury by infiltrating immune cells, such as macrophages, neutrophils, and T cells, as well as resident cells, including keratinocytes and mast cells (6), and either directly activate sensory receptors or sensitize them to subsequent stimuli (7). Moreover, prolonged inflammation can lead to central sensitization (in the spinal cord and brain) and bring about long-lasting chronic pain that persists after acute inflammation has resolved. Thus, a better understanding of the molecules involved in neuroinflammation may lead to therapeutic options for acute and chronic pain.Of the range of proalgesics known to promote pain, only nerve growth factor (NGF) and the glial cell line-derived neurotrophic factor family ligand (GFL) artemin have been shown to lead to cold hypersensitivity (8-11). Both are major components of the inflammatory soup and produce nociceptor sensitization and pain through their cognate cell surface rece...

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Lippoldt

Ongun

Kusaka

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Temperatures above this limit evoke robust background current in naïve Xenopus oocytes and HEK293T cells, preventing us from accurately assessing channel properties at higher temperatures. Therefore, although we do not rule out the possibility that sqTRPV1 and caTRPV1 may exhibit activation at temperatures higher than 46°C, they are the poorest heat sensors of all known vertebrate TRPV1 orthologs in the experimentally testable range (11,12,25).…”

Section: Discussionmentioning

confidence: 91%

“…Because, to our knowledge, all other tested vertebrate TRPV1 orthologs exhibit robust heat activation in the 28-46°C range (11,12,25), we attempted to reverse-engineer heat sensitivity in the squirrel and camel channels. The substitution of the whole cytosolic N terminus of sqTRPV1 (amino acids 1-430) with the same region from rTRPV1 (amino acids 1-428) resulted in heat-activated chimeras indistinguishable from the rat channel (Fig.…”

Section: Sqtrpv1 and Catrpv1 Are Ion Channels With Diminished Heatmentioning

confidence: 99%

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

Laursen

Schneider

Merriman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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...

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“…TRPV1 and TRPM8 are two TRP channels widely believed to serve this function. They are expressed in thermosensory neurons, are required for normal behavioral responses to thermal stimulation, and confer extraordinary temperature sensitivity on heterologous cells [6].Deciphering the role of a given TRP channel in thermosensation is complicated by several factors, including the fact that TRP channels integrate many signals [7] and interact with other proteins, including other TRP channels [8,9]. These factors affect interpretation of experiments performed in vivo and in heterologous systems, which are often somewhat responsive to temperature themselves [10].…”

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confidence: 99%

Molecules empowering animals to sense and respond to temperature in changing environments

Glauser

Goodman

2016

Current Opinion in Neurobiology

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Adapting behavior to thermal cues is essential for animal growth and survival. Indeed, each and every biological and biochemical process is profoundly affected by temperature and its extremes can cause irreversible damage. Hence, animals have developed thermotransduction mechanisms to detect and encode thermal information in the nervous system and acclimation mechanisms to finely tune their response over different timescales. While temperature-gated TRP channels are the best described class of temperature sensors, recent studies highlight many new candidates, including ionotropic and metabotropic receptors. Here, we review recent findings in vertebrate and invertebrate models, which highlight and substantiate the role of new candidate molecular thermometers and reveal intracellular signaling mechanisms implicated in thermal acclimation at the behavioral and cellular levels. Variations in ambient temperature have dramatic effects on animal behavior, survival, and reproduction. One dramatic example is the response of a waddle of Emperor penguins to variations in ambient temperature: the colder the temperature, the more likely penguins are to huddle and to huddle more tightly [1]. The social behavior of huddling is essential for thermoregulation, energy conservation, and to complete the breeding cycle. Thus, animals have evolved behavioral and metabolic strategies for minimizing their exposure to rapid fluctuations and for adapting to slow seasonal variations. Such thermal acclimation behaviors depend on the animal's ability to link information provided by specialized thermosensory neurons to appropriate behaviors. Laboratory studies in animals that are amenable to genetic dissection such as fruit flies, nematodes, and mice, have revealed many relevant sensory neurons and thermoreceptor proteins. In this review, we consider candidate thermoreceptor proteins and signaling pathways as well as molecular mechanisms for responding to changing thermal environments, highlighting recent key results and emerging opportunities for discovery in this area. Molecular basis of thermosensingTo function as a thermoreceptor, a protein or signaling pathway should exhibit several properties. First, the protein(s) should localize to the presumptive site of temperature-sensing within sensory neurons embedded in tissues subjected to thermal fluctuations [2 ]. Second, the proteins(s) should be required for cellular and behavioral responses to thermal cues. Third, the protein(s) should confer extraordinary temperature sensitivity on heterologous cells and, fourth, protein function should itself be exquisitely temperature-sensitive. Distinguishing ordinary from extraordinary thermal sensitivity is not easy, however. One useful rule of thumb is to focus on proteins or signaling pathways with Q 10 values that exceed those typical of biochemical reactions such as active transport of ions (ca. 3) across biological membranes [3]. Though imperfect (see Ref.[2 ]), the Q 10 metric is frequently used to assess the effect of temperature on cell func...

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The molecular and cellular basis of thermosensation in mammals

Cited by 67 publications

References 50 publications

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

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

Molecules empowering animals to sense and respond to temperature in changing environments

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