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

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.     

TRPV3 is a calcium-permeable temperature-sensitive cation channel

Transient receptor potential (TRP) proteins are cation-selective channels that function in processes as diverse as sensation and vasoregulation. Mammalian TRP channels that are gated by heat and capsaicin (>43 degrees C; TRPV1 (ref. 1)), noxious heat (>52 degrees C; TRPV2 (ref. 2)), and cooling (< 22 degrees C; TRPM8 (refs 3, 4)) have been cloned; however, little is known about the molecular determinants of temperature sensing in the range between approximately 22 degrees C and 40 degrees C. Here we have identified a member of the vanilloid channel family, human TRPV3 (hTRPV3) that is expressed in skin, tongue, dorsal root ganglion, trigeminal ganglion, spinal cord and brain. Increasing temperature from 22 degrees C to 40 degrees C in mammalian cells transfected with hTRPV3 elevated intracellular calcium by activating a nonselective cationic conductance. As in published recordings from sensory neurons, the current was steeply dependent on temperature, sensitized with repeated heating, and displayed a marked hysteresis on heating and cooling. On the basis of these properties, we propose that hTRPV3 is thermosensitive in the physiological range of temperatures between TRPM8 and TRPV1.     

The menthol receptor TRPM8 is the principal detector of environmental cold

Sensory nerve fibres can detect changes in temperature over a remarkably wide range, a process that has been proposed to involve direct activation of thermosensitive excitatory transient receptor potential (TRP) ion channels. One such channel--TRP melastatin 8 (TRPM8) or cold and menthol receptor 1 (CMR1)--is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below approximately 26 degrees C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons. However, some studies have questioned the contribution of TRPM8 to cold detection or proposed that other excitatory or inhibitory channels are more critical to this sensory modality in vivo. Here we show that cultured sensory neurons and intact sensory nerve fibres from TRPM8-deficient mice exhibit profoundly diminished responses to cold. These animals also show clear behavioural deficits in their ability to discriminate between cold and warm surfaces, or to respond to evaporative cooling. At the same time, TRPM8 mutant mice are not completely insensitive to cold as they avoid contact with surfaces below 10 degrees C, albeit with reduced efficiency. Thus, our findings demonstrate an essential and predominant role for TRPM8 in thermosensation over a wide range of cold temperatures, validating the hypothesis that TRP channels are the principal sensors of thermal stimuli in the peripheral nervous system.     

Thermal stimulation of taste

The first electrophysiological recordings from animal and human taste nerves gave clear evidence of thermal sensitivity, and studies have shown that as many as half of the neurons in mammalian taste pathways respond to temperature. Because temperature has never been shown to induce sensations of taste, it has been assumed that thermal stimulation in the gustatory system is somehow nulled. Here we show that heating or cooling small areas of the tongue can in fact cause sensations of taste: warming the anterior edge of the tongue (chorda tympani nerve) from a cold temperature can evoke sweetness, whereas cooling can evoke sourness and/or saltiness. Thermal taste also occurs on the rear of the tongue (glossopharyngeal nerve), but the relationship between temperature and taste is different there than on the front of the tongue. These observations indicate the human gustatory system contains several different types of thermally sensitive neurons that normally contribute to the sensory code for taste.     

The cells and logic for mammalian sour taste detection

Mammals taste many compounds yet use a sensory palette consisting of only five basic taste modalities: sweet, bitter, sour, salty and umami (the taste of monosodium glutamate). Although this repertoire may seem modest, it provides animals with critical information about the nature and quality of food. Sour taste detection functions as an important sensory input to warn against the ingestion of acidic (for example, spoiled or unripe) food sources. We have used a combination of bioinformatics, genetic and functional studies to identify PKD2L1, a polycystic-kidney-disease-like ion channel, as a candidate mammalian sour taste sensor. In the tongue, PKD2L1 is expressed in a subset of taste receptor cells distinct from those responsible for sweet, bitter and umami taste. To examine the role of PKD2L1-expressing taste cells in vivo, we engineered mice with targeted genetic ablations of selected populations of taste receptor cells. Animals lacking PKD2L1-expressing cells are completely devoid of taste responses to sour stimuli. Notably, responses to all other tastants remained unaffected, proving that the segregation of taste qualities even extends to ionic stimuli. Our results now establish independent cellular substrates for four of the five basic taste modalities, and support a comprehensive labelled-line mode of taste coding at the periphery. Notably, PKD2L1 is also expressed in specific neurons surrounding the central canal of the spinal cord. Here we demonstrate that these PKD2L1-expressing neurons send projections to the central canal, and selectively trigger action potentials in response to decreases in extracellular pH. We propose that these cells correspond to the long-sought components of the cerebrospinal fluid chemosensory system. Taken together, our results suggest a common basis for acid sensing in disparate physiological settings.     

A family of candidate taste receptors in human and mouse

The gustatory system of mammals can sense four basic taste qualities, bitter, sweet, salty and sour, as well as umami, the taste of glutamate. Previous studies suggested that the detection of bitter and sweet tastants by taste receptor cells in the mouth is likely to involve G-protein-coupled receptors. Although two putative G-protein-coupled bitter/sweet taste receptors have been identified, the chemical diversity of bitter and sweet compounds leads one to expect that there is a larger number of different receptors. Here we report the identification of a family of candidate taste receptors (the TRBs) that are members of the G-protein-coupled receptor superfamily and that are specifically expressed by taste receptor cells. A cluster of genes encoding human TRBs is located adjacent to a Prp gene locus, which in mouse is tightly linked to the SOA genetic locus that is involved in detecting the bitter compound sucrose octaacetate. Another TRB gene is found on a human contig assigned to chromosome 5p15, the location of a genetic locus (PROP) that controls the detection of the bitter compound 6-n-propyl-2-thiouracil in humans.     

A TAS1R receptor-based explanation of sweet 'water-taste'

'Water-tastes' are gustatory after-impressions elicited by water following the removal of a chemical solution from the mouth, akin to colour after-images appearing on 'white' paper after fixation on coloured images. Unlike colour after-images, gustatory after-effects are poorly understood. One theory posits that 'water-tastes' are adaptation phenomena, in which adaptation to one taste solution causes the water presented subsequently to act as a taste stimulus. An alternative hypothesis is that removal of the stimulus upon rinsing generates a receptor-based, positive, off-response in taste-receptor cells, ultimately inducing a gustatory perception. Here we show that a sweet 'water-taste' is elicited when sweet-taste inhibitors are rinsed away. Responses of cultured cells expressing the human sweetener receptor directly parallel the psychophysical responses-water rinses remove the inhibitor from the heteromeric sweetener receptor TAS1R2-TAS1R3, which activates cells and results in the perception of strong sweetness from pure water. This 'rebound' activity occurs when equilibrium forces on the two-state allosteric sweet receptors result in their coordinated shift to the activated state upon being released from inhibition by rinsing.     

The development of taste transduction and taste chip technology

Taste is one of important sensations. The primary taste sensations commonly are categorized as sweet, acid, bitter, salty and umami, of which various tastes are composed. The sensation of taste is initiated by the interaction of tas- tants with receptors and ion channels in the apical micro- villi of taste receptor cells (TRCs) when some sapid molecules (tastants) dissolve in saliva. Subsequently, through a cellular signaling pathway (TRC depolarization and Ca2+ release) gustatory signals a…     

西施舌的营养药用价值及开发利用

西施舌（Coelomactra antiquata）是海产双壳类蛤蜊科软体动物,个体较大、肉质细嫩、滋味鲜美、营养丰富,是早负盛名的筵席珍品佳肴,具有重要的食用和药用价值。本文综述了西施舌的营养与药用价值,以及西施舌医药应用的开发前景。以其为西施舌的营养与药用的开发利用提供思路。     

口感导向的烟气甜香味成分的剖析

对云南红河烟叶单料烟的烟气甜香味成分进行了分析,利用凝胶渗透色谱(GPC)分离其烟气粒相物的水溶性组分,并对所得流分进行感官味觉评价,同时结合电子舌评价结果定位出甜香味特征流分,采用气相色谱-质谱法(GC/MS)定性甜香味流分中的化学成分.结果表明:特征流分中具有甜香味的成分主要为吡喃酮类、呋喃类、呋喃酮类和环戊烯酮类化合物.该研究方法可为剖析烟气中关键的甜香味成分和提高卷烟的感官舒适性提供一定的参考价值.     

Requirement of TRPC channels in netrin-1-induced chemotropic turning of nerve growth cones

Ion channels formed by the TRP (transient receptor potential) superfamily of proteins act as sensors for temperature, osmolarity, mechanical stress and taste. The growth cones of developing axons are responsible for sensing extracellular guidance factors, many of which trigger Ca2+ influx at the growth cone; however, the identity of the ion channels involved remains to be clarified. Here, we report that TRP-like channel activity exists in the growth cones of cultured Xenopus neurons and can be modulated by exposure to netrin-1 and brain-derived neurotrophic factor, two chemoattractants for axon guidance. Whole-cell recording from growth cones showed that netrin-1 induced a membrane depolarization, part of which remained after all major voltage-dependent channels were blocked. Furthermore, the membrane depolarization was sensitive to blockers of TRP channels. Pharmacological blockade of putative TRP currents or downregulation of Xenopus TRP-1 (xTRPC1) expression with a specific morpholino oligonucleotide abolished the growth-cone turning and Ca2+ elevation induced by a netrin-1 gradient. Thus, TRPC currents reflect early events in the growth cone's detection of some extracellular guidance signals, resulting in membrane depolarization and cytoplasmic Ca2+ elevation that mediates the turning of growth cones.     

Pinacidil,a K<Subscript>atp</Subscript> channel opener,identified as a novel agonist for TRPA1

The transient receptor potential Ankyrin 1(TRPA1) cation channel is activated by various pungent and irritant compounds,and it also mediates the perception of noxious cold.Identification of different agonists for this channel is important for understanding its activation mechanism.Therefore,a screen for novel TRPA1 agonists was performed using an agonist-induced calcium influx assay.Out of 90 compounds screened,pinacidil was identified as a novel agonist for this channel.Pinacidil is a known opener of the K atp channel,for which it has an EC50 value of 1-3 μmol/L.In comparison,the EC50 value of pinacidil for TRPA1 is relatively high(260 μmol/L).Recombinant HEK-TRPA1 cells did not respond to P1075,another K atp channel opener,suggesting that the effect of pinacidil on TRPA1 was highly specific.Further studies revealed that the agonist activity of pinacidil could be blocked by the TRP channel inhibitors,ruthenium red and HC-030031.Using glutathione(GSH) and site-specific mutagenesis,we demonstrated that pinacidil could activate TRPA1 by covalent modification of the critical amino acids C619,C639 and C663 in the N-terminus of TRPA1.     

The receptors and coding logic for bitter taste

The sense of taste provides animals with valuable information about the nature and quality of food. Bitter taste detection functions as an important sensory input to warn against the ingestion of toxic and noxious substances. T2Rs are a family of approximately 30 highly divergent G-protein-coupled receptors (GPCRs) that are selectively expressed in the tongue and palate epithelium and are implicated in bitter taste sensing. Here we demonstrate, using a combination of genetic, behavioural and physiological studies, that T2R receptors are necessary and sufficient for the detection and perception of bitter compounds, and show that differences in T2Rs between species (human and mouse) can determine the selectivity of bitter taste responses. In addition, we show that mice engineered to express a bitter taste receptor in 'sweet cells' become strongly attracted to its cognate bitter tastants, whereas expression of the same receptor (or even a novel GPCR) in T2R-expressing cells resulted in mice that are averse to the respective compounds. Together these results illustrate the fundamental principle of bitter taste coding at the periphery: dedicated cells act as broadly tuned bitter sensors that are wired to mediate behavioural aversion.     

基于TRPM8通道薄荷醇对小鼠气道平滑肌影响的实验研究

目的：基于TRPM8通道研究薄荷醇(Menthol)对小鼠气道平滑肌的影响。方法：运用平滑肌张力测定技术检测Menthol对TRPM8野生型(TRPM8+/+)和敲除型(TRPM8-/-)小鼠离体气道平滑肌的张力改变。结果：1. Menthol呈浓度依赖性地引起TRPM8+/+小鼠气道平滑肌舒张,而在TRPM8-/-小鼠此作用不明显。结论：Menthol可通过TRPM8通道改变小鼠气道平滑肌张力     

Spider toxins activate the capsaicin receptor to produce inflammatory pain

Bites and stings from venomous creatures can produce pain and inflammation as part of their defensive strategy to ward off predators or competitors. Molecules accounting for lethal effects of venoms have been extensively characterized, but less is known about the mechanisms by which they produce pain. Venoms from spiders, snakes, cone snails or scorpions contain a pharmacopoeia of peptide toxins that block receptor or channel activation as a means of producing shock, paralysis or death. We examined whether these venoms also contain toxins that activate (rather than inhibit) excitatory channels on somatosensory neurons to produce a noxious sensation in mammals. Here we show that venom from a tarantula that is native to the West Indies contains three inhibitor cysteine knot (ICK) peptides that target the capsaicin receptor (TRPV1), an excitatory channel expressed by sensory neurons of the pain pathway. In contrast with the predominant role of ICK toxins as channel inhibitors, these previously unknown 'vanillotoxins' function as TRPV1 agonists, providing new tools for understanding mechanisms of TRP channel gating. Some vanillotoxins also inhibit voltage-gated potassium channels, supporting potential similarities between TRP and voltage-gated channel structures. TRP channels can now be included among the targets of peptide toxins, showing that animals, like plants (for example, chilli peppers), avert predators by activating TRP channels on sensory nerve fibres to elicit pain and inflammation.     

优质香米新品种香宝三号的选育

香宝三号系河南省信阳农专特种稻育种室采用马坝香糯/桂朝二号杂交育成.该品种属中灿迟熟粘质特种稻优质香米新品种.其株形集散适中,中矮秆.叶片挺伸、长宽中等,叶色淡绿.表现高产稳产,米质特优,耐肥抗倒,抗病、抗虫性较强.精米蛋白质含量7.83%,直链淀粉含量15.76%,糊化温度低,胶稠度软.蒸米香味纯正,浓淡适宜,略具甜味,质地软而不粘,韧、滑、润、油光发亮,适口性极佳.在生产与市场上,深受稻农和消费者欢迎.     

Climate sensitivity constrained by CO2 concentrations over the past 420 million years

A firm understanding of the relationship between atmospheric carbon dioxide concentration and temperature is critical for interpreting past climate change and for predicting future climate change. A recent synthesis suggests that the increase in global-mean surface temperature in response to a doubling of the atmospheric carbon dioxide concentration, termed 'climate sensitivity', is between 1.5 and 6.2 degrees C (5-95 per cent likelihood range), but some evidence is inconsistent with this range. Moreover, most estimates of climate sensitivity are based on records of climate change over the past few decades to thousands of years, when carbon dioxide concentrations and global temperatures were similar to or lower than today, so such calculations tend to underestimate the magnitude of large climate-change events and may not be applicable to climate change under warmer conditions in the future. Here we estimate long-term equilibrium climate sensitivity by modelling carbon dioxide concentrations over the past 420 million years and comparing our calculations with a proxy record. Our estimates are broadly consistent with estimates based on short-term climate records, and indicate that a weak radiative forcing by carbon dioxide is highly unlikely on multi-million-year timescales. We conclude that a climate sensitivity greater than 1.5 degrees C has probably been a robust feature of the Earth's climate system over the past 420 million years, regardless of temporal scaling.     

Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli.

Sour taste is initiated by protons acting at receptor proteins or channels. In vertebrates, transduction of this taste quality involves several parallel pathways. Here we examine the effects of sour stimuli on taste cells in slices of vallate papilla from rat. From a subset of cells, we identified a hyperpolarization-activated current that was enhanced by sour stimulation at the taste pore. This current resembled Ih found in neurons and cardio-myocytes, a current carried by members of the family of hyperpolarization-activated and cyclic-nucleotide-gated (HCN) channels. We show by in situ hybridization and immunohistochemistry that HCN1 and HCN4 are expressed in a subset of taste cells. By contrast, gustducin, the G-protein involved in bitter and sweet taste, is not expressed in these cells. Lowering extracellular pH causes a dose-dependent flattening of the activation curve of HCN channels and a shift in the voltage of half-maximal activation to more positive voltages. Our results indicate that HCN channels are gated by extracellular protons and may act as receptors for sour taste.     

糯米酒发酵工艺优化

以优质糯米为原料对糯米酒发酵工艺参数进行优化,比较了3种酒曲的发酵性能,通过正交试验优化糯米酒生产工艺.结果表明,甜酒曲为最佳发酵酒曲,糯米酒生产的最佳工艺为糯米蒸煮15 min,酒曲量0.5%,发酵时间为48 h,料水比为10∶3（g∶m L）,在30℃下恒温发酵生产的糯米酒口感适宜,香气浓郁.     

TRP channels as cellular sensors

TRP channels are the vanguard of our sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory apparatus for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.