Transient Receptor Potential channels: What's happening? Reflections in the wake of the 2009 TRP...

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Channels 4:2, 1-12; March/April 2010; © 2010 Landes BioscienceMeeting RepoRt Meeting RepoRt

Background

The Transient Receptor Potential (TRP) family of ion chan-nels is named after the Drosophila melanogaster ion channel that is mutated in the trp gene. This mutant was first reported by Minke.1 Subsequent works by Montell et al. established a solid foundation for this remarkable functional family of ion chan-nels.2-4 TRPs are non-selective cation channels involved not only in a variety of physical and chemical sensation but also in cell signaling, development, and in many pathological conditions.5 Since their discovery, the TRP channels have been investigated by many researchers and these channels have received attention both in basic research as well as in clinical research. The TRP meet-ing that is the topic of this report took place in the Karolinska Institutet, Stockholm, Sweden from the 25th to the 27th Sept 2009

*Correspondence to: Chandan Goswami; Email: [email protected] / Md. Shahidul Islam; Email: [email protected]: 02/08/10; Revised: 02/10/10; Accepted: 02/10/10Previously published online:www.landesbioscience.com/journals/channels/article/11478

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(Fig. 1). The meeting was organized by Md. Shahidul Islam and Craig Montell. Details of this meeting are available from this site http://trp.islets.se from where the abstracts can be downloaded. As the interest in the TRP channels is growing in an exponential rate, summarizing diverse aspects of the TRP channels discussed in this meeting is a difficult task. Here, we have tried to identify some of the highlights of this meeting and have discussed some of the crucial issues.

Scientific Highlights

Role of TRP channels in thermosensation. The abilities of sensing and differentiating environmental temperatures are important functions performed by almost all organisms. However, different organisms handle this fundamental function by differ-ent mechanisms and by recruiting different sets of molecules that can sense different temperatures.6,7 In this context, TRP channels are particularly interesting since some TRP channels can be activated by different temperatures.8-10 Such thermo-sen-sitive TRP channels are quite selective for different temperature ranges in which they can be activated.11 Such temperature ranges cover from noxious cold to noxious heat. It has, therefore, been speculated that the thermo-sensitive TRP channels are respon-sible for thermosensation and for the maintenance of the normal body temperature.12-14 However, the molecular mechanisms by which these thermo-sensitive TRP channels recognize different temperatures remain unanswered.15,16 Recent electrophysiologi-cal and knockout studies show that the molecular mechanism of thermosensation can not be solely dependent on the TRP channels. Molecules other than TRP channels are also involved in this process in a more complex manner than it was thought before.17-21 In fact many of the animals lacking TRP channels show normal thermosensation.22,23 On the other hand, some ani-mals genetically lacking molecules other than the TRP channels also manifest altered thermosensation. For example mice lacking P2Y2 receptor reveals abnormal thermal nociception.24 Taking together, these studies indicate that a complex network is operat-ing behind the molecular mechanisms of thermosensation.

Previously it has been shown that swapping the C-terminal cytoplasmic domain of a cold receptor (TRPM8) with a hot receptor (TRPV1) makes the cold receptor recognize high tem-perature and vice versa.25 This indicated that the C-terminal

TRP channelsWhat’s happening? reflections in the wake of the 2009 TRP

meeting, karolinska institutet, stockholmChandan goswami1,* and Md. Shahidul islam2,*

1national institute of Science education and Research; institute of physics Campus; Sachivalaya Marg, Bhubaneswar india; 2Department of Clinical Sciences and education; Södersjukhuset Karolinska institute; Stockholm, Sweden; and Uppsala University Hospital; Uppsala, Sweden

Key words: TRP channel, calcium, thermosensation, rhodopsin, channel gating, membrane curvature, steroids, hormone, insulin

More than 150 participants from 25 countries gathered in Stockholm during 25th to 27th Sept 2009 to attend the meeting “tRp channels: from sensory signaling to human disease” and enjoyed an international, intensive and vibrant meeting. this meeting shed lights on the recent advances made in this field of research in different sectors of biology, and identified directions for future research and the areas where tRp channels could be used as potential targets for prevention and treatment of human diseases. the participants of this meeting shared their recent largely unpublished data, state-of-the-art techniques and their critical views which would push research in this field forward in the new decade. Another major outcome of this meeting was the realization that extensive work remains to be done to develop the necessary tools and enhance the quality of research in this area so that the prevailing controversies can be resolved. in this report we summarize the latest scientific excitements, some critical issues, as well as some future directions for research that were addressed and discussed in this meeting.

2 Channels Volume 4 issue 2

short-openings that occur first and that these short-openings are important for initiating the current. From these features, a simple two step model can be built:

C = f(temperature)

⇋ Oshort

⇋ Olong

This model suggests that the 1st step is brief in duration, tem-perature-sensitive and it triggers the thermo sensor. In contrast, the second step is insensitive to temperature but it stabilizes the conductance state.

Interestingly, they found that in case of a triple mutant of rat TRPV1 (L268K + N652T + Y653T), the long-openings are completely lost. In this regard it is noteworthy that two of these mutants are located between the pore-loop and the 6th transmem-brane domain (at the extra-cellular site) of TRPV1. However, the results they obtained with TRPV1 are different from what they found previously with TRPV3. In case of TRPV3, they found that the mutations that are required for heat activation are located in the pore region.31 So it is possible that the outer part of the TRPV1 pore can stabilize the opening. Allosteric interac-tion with the intracellular proteins and/or extra-cellular matrix proteins can also affect the pore openings.

Rhodopsin as heat-sensor. This meeting witnessed an alternative hypothesis proposed by Craig Montell regarding the heat-sensing of TRP channels. His co-workers showed that Drosophila mela-nogaster larvae which carried mutation in TRPA could not distin-guish temperature between 18°C (a preferable temperature) and 24°C (a non-preferable temperature).35 Their subsequent studies indicate that the signaling event involved in this PLC-mediated thermo-sensing cascade is very similar to the phototransduc-tion cascade in drosophila. Moreover, they found that the same Gq proteins are involved in the phototransduction as well as in thermosensing events.36 In fact they found that drosophila larvae carrying mutation in Rhodopsin (P332G) actually mimics the phenotype of TRPA mutant in terms of thermo-sensation. This prompted researchers to explore if Rhodopsin, which is involved in light-sensing, is also involved in the process of thermosensa-tion. They found that indeed Rhodopsin can sense heat and amplify the thermo-signaling events. Rhodopsin is regulated by the visual cycles, available concentration of the cis-trans isoforms in the retina and also by the enzymes that control retinal metabo-lism. In addition, several studies with Rhodopsin indicate that its structure-function relationship is complex and its sequence is highly variable in different organisms. The sequence analysis of Rhodopsin indicates the existence of divergent selection pressures where dim light may not be the prime selection force for molecu-lar evolution.37 In this context, it is important to note that many primitive organisms growing in very dark conditions also possess Rhodopsin in their genome. Thus it might be possible that the primitive role of Rhodopsin is actually thermo-sensation rather than the photosensation, and that it might have evolved due to an adaptive pressure to distinguish different temperatures.

The study by Montell and his colleagues raises an important question: does Rhodopsin act as a primitive light sensor or primi-tive thermo sensor or both? This question also leads to a bigger question: Is there any dedicated and separate molecular machinery

cytoplasmic domain is important for the thermosensitivity/ther-moactivation. It has been proposed that in case of the thermo-sensitive TRP channels, the thermosensitivity is a function of their voltage sensitivity.26-29 Though a lot of investigations have been done on the thermosensitive TRP channels, the mechanism by which a single TRP channel senses different temperatures remains largely unclear.28,30 Hence, the molecular mechanisms by which TRP channels contribute to the thermosensation and/or thermoactivation are currently an area of active research.31-33 Here we discuss the latest developments regarding the mecha-nisms of thermoactivation and thermosensation in the context of the TRP channels.

Thermal conductance is a two step function of temperature. Generally the heat activated channels have a conductance of 30–40 pS and the single channel conductance is not directly temperature dependent. However, the probabilities of having an ion channel in open state correlate with the temperatures. Previously, “multiple open states” has been proposed to explain the activation of TRPV1.16,34 In this meeting, Ardem Patapoutian showed single channel recordings of rat TRPV1 that shed new lights on the nature of the thermal conductance of TRPV1. In 30°C, the wild type channel forms a typical pattern of currents which consists of both long- and short-openings. However, in reduced temperature, the long-openings are reduced while short-openings are unaffected. In other words, increasing temperature increases the long-openings. However, the short-openings should be stabilized in order to have subsequent long-openings. Based on these observations, he proposed that the thermal conductance (C) is a reversible function (f) of temperature and that it is the

Figure 1. “tRp channels: from sensory signaling to human disease, 25th–27th Sept 2009”. the meeting started with a social mingling at the prestigious City Hall of Stockholm on a sunny evening of 25th Sept 2009. the scientific sessions in next two days (total 19 talks and 75 posters) revealed the current state of research in this field in great details. in addition to the posters, the speakers presented their in-depth studies, their life-long experiences and shared their unpublished works with the audience. this meeting attracted participants from a variety of sectors as evident from the highly heterogeneous nature of the backgrounds of the participants: male and female participants, gray-haired established scientists and young students from 25 different countries from different continents made it a truly international meeting.


In this regard, progresses made by David Julius and his group are impressive. They isolated a toxin called DkTx from the Earth Tiger Tarantula (Ornithoctonus huwena). The toxin belongs to the Inhibitor-Cystine-Knot (ICK) family of toxins and Vanilotaxon (VaTx). DkTx can activate rat TRPV1 channel but cannot activate Xenopus TRPV1 and Kv1 (a voltage-sensitive cation channel). Thus, this toxin offers a possibility to perform the chimeric study between rat TRPV1 and Xenopus TRPV1. This study shows that rat TRPV1 mutant A657P is insensitive and Xenopus TRPV1 mutant P663A is sensitive to this toxin. They also found that the recombinant toxin or even a part of this toxin is as effective as the purified toxin. The toxin binds to the pore region of the TRPV1 and the effect of this toxin can be blocked by the ruthidium red. Interestingly, this toxin can be expressed as Histidine tag and the tagged toxin can also be used to pull down/purify the full-length TRPV1. However, the most interesting aspect of this toxin is its effect on the TRPV1 channel. Apparently, the toxin activates TRPV1-expressing cells for a long time, even after the washout, as observed from the Ca2+-imaging assays. Apparently, the toxin fixes rat TRPV1 channel in the open stage for a long time. Thus, the toxin seems to be a conformation-sensitive reagent and/or it stabilizes the “open-stage” of the channel. Therefore, this toxin appears to be an ideal reagent to study the properties of TRPV1 at its “open-state”.

Does membrane structure and composition influence TRP channels? TRP channels are embedded in the lipid bilayer but whether or not membrane environment influences TRP chan-nels is unclear. It is, however, known that some lipids can specifi-cally activate or inhibit some of the TRP channels. For example, sphingolipids and their derivatives can activate TRPM3 and TRPC1.46,47 Human TRPM3 is inhibited by cholesterol (abstract # 27, Navlor et al.).48 Specific lipid binding proteins can also act as specific subunits of TRP channels and can thereby regulate the channel activity to a variable extent. For example, Pirt, a phosphoinositide-binding protein, functions as a regulatory sub-unit of TRPV1.49 Even, enzymes that regulate lipid metabolism are known to regulate some TRP channels. For example, phos-pholipases, PKC and sphingosine kinase are known to modu-late the Ca2+-entry via TRP channels.48,50-53 Effect of membrane composition on the TRP channels is also evident from the fact that altering the membrane composition, either by depletion or addition/saturation of membrane cholesterol affects the proper-ties of some TRP channels and/or physiological functions medi-ated by these channels.34,54-56 The notion that membrane lipid composition and membrane structure (membrane microdomain curvature) can affect TRP channels is favored by many. Indeed, results from Minke’s lab suggested that the “lipid packing” of the membrane as well as the “channel-plasma membrane interface” might be important for the activation of TRP channels (abstract # 41, Minke B).57,58 They propose that PLC, which converts PIP

2

to diacylglycerol (DAG), induces alteration in the membrane structure and forms a bended curvature in the small lipid mem-brane microdomain regions. This is due to the fact that DAG is smaller in structure when compared to the PIP

2 due to the loss

of some head portion.59-61 Thus, PLC-mediated changes in the TRP activity might be due to the direct effects of changes in

for sensation of physical stimuli (like temperature and light) or are there overlapping molecular mechanisms that are common for both thermosensation as well as for photosensation? In this context, a recent study from Ward et al. is relevant.38 C. elegans, a nematode that lives in soil is generally believed to lack photosen-sation. However, Ward et al. demonstrate that light stimuli elic-its a negative phototaxis in this organism in a dose-dependent manner and that cyclic guanosine monophosphate (cGMP)-sensitive cyclic nucleotide-gated (CNG) channel is important for this behavior.38 This not only reveals conservation in pho-totransduction between worms and vertebrates but also suggests that animals living in dark environments without light-sensing organs should not be presumed to be light-insensitive. This also indicates that certain second messenger molecules may form a common pathway that can be useful for both phototransduction as well as for thermotransduction.

Recent studies regarding the “gating of thermo-sensitive TRP channels”. Understanding the gating mechanism of thermo-sensitive TRP channels remains a challenge. For exam-ple, TRPV1 is characterized by having gating mechanisms, which shows sensitivity to heat. TRPV1 has a very high tem-perature coefficient (Q10 value) of around 27.34 This value is much greater than 2, the standard Q10 value known for the majority of biochemical reactions including most of the ion-channel-activities.9 Experiments with rapid temperature jump shows that TRPV1 activation is a relatively rapid event in which TRPV1-mediated currents reach a plateau in less than 500 ms. Conversely, it has been shown that lower temperature reduces the probability of channel opening.39 Both voltage-sensitivity and allosteric modulation have been proposed to be the underly-ing mechanism behind the gating of the thermo-sensitive TRP channels.26,40-43 For cold channels like TRPM8, it has been shown that menthol and cold-mediated activation takes place through shifts in its voltage-activation curve which causes the channel to open at physiological membrane potentials.29 Even some specific inhibitors exert their inhibitory effects by shift-ing the voltage dependence of TRPM8 activation towards more positive potentials.

In this context, results presented by Rosenbaum et al. indi-cate the importance of the S6 transmembrane segment of the thermosensor channels in gating mechanisms utilized by tem-perature and capsaicin.44,45 To locate the “gate” present in the thermosensor, they introduced Cys residues (point mutations) in S6 segment of the TRPV1 channel and characterized the acces-sibility of Cys residues to thiol-modifying agents. They demon-strate that the pore-forming S6 segment has helical structures and this segment is responsible for both capsaicin-binding and sensing of different temperatures. There are two constrictions present in the pore: one that impedes the access of large mol-ecules and the other that hampers the access of smaller ions and constitutes an activation gate for these channels. In spite of a great deal of efforts invested by many groups, further under-standing of the gating mechanism of the thermosensitive TRP channels remains elusive. One main difficulty is the very short time period that can be considered as the “open-state”, and the presence of multiple intermediate states.


induced by TRPC1 is regulated by the presence or absence of TRPC1 in the lipid raft.67,68

Another example of regulation of TRP channels by lipid structures is TRPM8, which is mainly localized in the cholesterol-rich lipid rafts.54 TRPC3, another TRP chan-nel shows enhanced membrane expression in response to cholesterol. Graziani et al. demonstrated that cholesterol loading activates cellular TRPC3 conductance.69 This cholesterol-induced membrane conductance exhibited a current-to-voltage relationship similar to that observed upon PLC-dependent activation of TRPC3 channels. Shoeb et al. also detected three different TRP channels (TRPC1, TRPC3 and TRPC6) in the sperm membrane rafts (abstract # 6, Shoeb et al.). As lipid rafts have a dis-tinct lipid composition and structure, it is plausible that TRP channels behave differently when they are located outside the lipid rafts and/or when the composition of the rafts are changed. Indeed, such differences have been observed, at least for TRPM8 and TRPV1.34,54,55,70 It has been noted that menthol- and cold-mediated responses of TRPM8 are potentiated when the lipid raft association of the channel is prevented.54 Disruption of lipid rafts shifts the TRPM8 activation threshold to a warmer temperature. These results suggest that the different lipid membrane environments affect the cold sensing properties of TRPM8. In case of TRPV1, cholesterol depletion results in signifi-cant reduction in the amplitude of the capsaicin currents.55 Considering the similarities among these TRP channels, it is tempting to speculate that lipid environment modu-lates other TRP channels, particularly the TRP channels involved in thermosensation and/or mechanosensation.

Not all TRP channels have been tested for their sensi-tivity to mechanical stimulation, and the number of TRP channels where an ionic conductance can be activated by

mechanical force is low. Among all TRP channels, only the TRPV4 has been reported to mediate Ca2+ influx in response to mechanical stimulation. Considering the fact that “mechanical stimulation” is not a well-characterized and well standardized protocol that can be employed by all investigators, it is at pres-ent difficult to predict if and to what extent other TRP channels can respond to mechanical stimulation. Identification of TRP channels that can be activated by mechanical force is of clinical importance since many of the TRPs (for example different TRPC channels) are present in the cardiac and pulmonary systems and they have been implicated in mediating cardiac diseases.71

In this context, two groups have explored if mechanical pres-sure can activate TRPC5 and TRPC6 channels.72,73 Gomis et al. demonstrated that application of water pressure through patch pipette induces membrane stretch which activates TRPC5. Interestingly they found that reducing the phosphatidylinositol 4,5-bisphosphate (PIP

2) levels in the membrane actually abol-

ishes the hypotonicity-evoked activation of TRPC5. Gudermann et al. explored if direct membrane stretch can activate TRPC6.73 They reported that application of pressure on the patch con-taining TRPC6 does not activate the channel. It has been pro-posed that stretching and/or alteration of membrane structure is

the membrane as well as some indirect effects. These changes include interaction at the membrane-channel interface, the local bending of the membrane, the curvature of the lipid membrane and also the electrostatic properties of the lipid bilayer (Fig. 2).61,62 Furthermore, the alteration of the membrane composi-tion may lead to the removal of open channel block (OCB), a process by which ions bound to the inner side of a channel get released.57,58

A number of studies have indicated that TRP channels are also localized in specific regions of the plasma membrane micro-domain commonly known as lipid rafts that scaffold several other signaling complexes.47,63-65 For example, TRPM7 in vas-cular smooth muscle cells is localized in the fraction that cor-responds to the caveolae fraction. Immunofluorescence analysis also confirms that TRPM7 co-localizes with flotillin-2, a marker of lipid rafts.63 At very low concentrations, free cholesterol can alter Ca2+ entry via TRPC1, in cholesterol depleted polymor-phonuclear neutrophils.64 It has been observed that TRPC1 redistributes into the raft fractions in response to cholesterol. Localization of TRPC1 in the lipid raft in response to ketocho-lesterol has been observed in THP-1 monocytic cells.66 Another report indicates that in the cell, the store-operated Ca2+ entry

Figure 2. Membrane alteration-induced activation of tRp channels. (A) phos-pholipase C activation converts membrane lipids to inositol 1,4,5-triphosphate (ip3) and 1,2-diacyl glycerol (DAg). (B) this conversion induces shortening of certain membrane lipids and thus alters the lipid packing at the inner surface of the membrane micro-domain. (C) Changes in the membrane curvature and in the lipid-tRp channel interactions result in conformational changes leading to the opening of tRp channels. (D) Change in the membrane curvature can also affect the “open channel block” by forcefully removing the metal ions from the channels. this allows further opening of the tRp channels.


TRPM8 expression is important for the progression of prostate cancer towards androgen-independence.

Besides regulating the expression of TRP channels, steroids can also elicit some fast responses suggesting that the steroids may act directly on the TRP channels without involving gene transcription.77,78,89 In this respect, only a few studies have exam-ined the mechanisms underlying the rapid action of steroids on TRP channel. These rapid effects of steroids on TRP channels appear to be both indirect and/or direct.

Shoeb et al. reported that the level of TRPC1 within the lipid raft in the capacitated sperm decreases after estrogen treatment (abstract # 6, Shoeb et al.). This suggests that a change in the membrane structure/fluidity may explain the rapid action of ste-roids. Using renal late distal convoluted tubules (DCT2s) and connecting tubules (CNTs), Praetorius et al. demonstrated that the intracellular free Ca2+ concentration is increased by progester-one (10-11 to 10-9 M) and estrogen (10-9 to 10-7 M) (Hofmeister and Praetorius, abstract # 71, Hofmeister et al.).90 Interestingly, this increased Ca2+-influx cannot be blocked by the application of classical estrogen receptor inhibitors e.g., mifepristone and fulvestrant, suggesting that the effect is not mediated by the classical estrogen receptors. Further studies suggested that this rapid action of estrogen is due to TRPV5, and that the localiza-tion of TRPV5 in the apical membrane is increased by estrogen treatment. This study suggests involvement of a complex cellular signaling cascade that leads to the rapid effect of estrogen. Cao et al. reported similar rapid estrogen signaling events that regu-late Mg2+-homeostasis via TRPM6.89 Another exemplary effect of steroids on TRP channels has been presented by Yogi et al. (abstract # 37, Yogi et al.). They reported that aldosterone (100 µM) can stimulate annexin 1 and calpain, downstream targets of TRPM7. Similarly, Navlor et al. reported that TRPM3 can be stimulated by neurosteroid pregnenolone sulphate (Navlor et al. abstract # 27, Navlor et al.). Whether pregnenolone sulphate acts as a direct agonist for TRPM3 is, however, not clear. Interestingly this pregnenolone sulphate-evoked current via TRPM3 can be inhibited by cholesterol. Considering the complexity of steroid bio-synthesis and its degradation, and the diverse ways by which the steroids (also various lipids) can influence several TRP chan-nels, in-depth understanding of these cross talks appears to be important.

Insulin. Previous studies demonstrated that some TRP chan-nels e.g., TRPM2, TRPM6, TRPM7 and TRPC4 may be asso-ciated with the development of diabetes.91 Subsequent studies confirmed that many of the TRP channels are expressed in pan-creatic β-cells, and insulin secretion can be regulated by these TRP channels.92-94 Even, genetic variants of some TRP chan-nels have been associated with the development of diabetes.95 Recent studies also suggest that insulin can regulate TRPC3 and TRPV1.96,97 In this context, recent works from Nair et al. (abstract # 54, Nair et al.) suggest that TRPM7 is another TRP channel where insulin may have an effect. Using TIRF (Total Internal Reflection Fluorescence) microscope, they demonstrate that trafficking of TRPM7-containing vesicles towards plasma membrane was increased by insulin. They also demonstrate that

involved in the activation of mechanosensitive TRP channels.74 How mechanical force actually activates these mechanosensitive TRP channels and results in conductance is an important ques-tion that remains to be answered.

TRP channels as novel targets for hormone actions. TRP channels have been linked to the development of many patho-logical conditions including some disease syndromes.75 In this respect, only a few new studies have demonstrated that some hor-mones indeed regulate several TRP channels both directly, and indirectly by altering their expression level.76 For example, natu-rally occurring steroid pregnenolone sulfate activates TRPM3 directly.77,78 In contrast, erythropoietin enhances Ca2+-influx in human erythroid cells by indirect activation of TRPC3 channel.79 Although the complex network of different hormones acting on different TRP channels has not yet been explored, at present it appears that TRPV1 is a common target for many hormones. For example, prolactin,80 endothelin81 and neurokinin82 exert regula-tory effect on TRPV1. Even the hunger-inducing hormone ghre-lin potentiates TRPV1 in supraoptic magnocellular neurones, as the effect of this hormone on miniature excitatory postsynaptic currents is attenuated in TRPV1 knockout mice (trpv1-/-).83 In many cases, both development of the hormone producing tis-sues and the secretion of hormones are also regulated by TRP channels. Thus, a multidirectional regulation of TRP channels and hormonal actions are important as such cross-talks regulate diverse functions like Ca2+ re-absorption, aging and many other biological processes. In the following paragraphs we have dis-cussed some of the cross talks that have attracted attention in the recent years.

Estrogen and other steroids. According to the classical view, estrogen acts as a transcriptional regulator and it alters the expres-sion of many genes. It is noteworthy that the expression pattern of different TRP channels and steroid receptors show strong correla-tion. Indeed, a large number of studies indicate that estrogen and other steroids not only regulate the expression of TRP channels but also participate in cross-talks with many TRP channels. For example, expression of TRP4 in bovine aortic endothelial cells is significantly downregulated by application of β-estradiol.84 In contrast, estrogen enhances the expression of TRPV1 channel in c-fibres.85 Interestingly, capsaicin, the agonist of TRPV1 is also known to induce expression of androgen receptor in prostate LNCaP cells suggesting that TRP channels and steroid receptors can regulate each other and can form feedback regulatory loops.86 Such cross talks between estrogen (and other steroids) and TRP channels have clinical implications for several reasons. The expression of some TRP channels are altered in different cancers which are considered as hormone-receptor-positive cancers (these cancers rely on supplies of the steroid hormones to grow) and the channels have been linked to the progression of the cancer tissue to hormone-independence.76 For example, breast cancer epithelial primary culture (hBCE) reveals enhanced expression of TRPC3 and TRPC6.87 It is also reported that TRPM8-specific mRNA is overexpressed in prostate cancer. The expression of TRPM8 requires a functional androgen receptor as trpm8 gene seems to be androgen-responsive.88 This androgen mediated regulation of

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the complexity of hormone biology and the diverse manners by which the hormones influence multiple TRP channels, understanding these complicated networks is important for both basic research as well as for clinical purposes.

Physiological functions of endovanilloids. Most of the ligands (like Capsaicin, RTX, menthol etc.,) which are routinely used to characterize the respective TRP channels are exogenous in nature. Therefore, response to these com-pounds does not reflect the actual regulation of the TRP channels in vivo. The compounds that are present in vivo and can activate TRP channels are the most important as such compounds may directly regulate cellular metabolism and physiology. Among many endogenous compounds,

endovanilloids drew attention of many since it has been noted that some of the lipid derivatives containing vanilloid moieties can activate TRPV channels.111 At present, several endovanilloids (e.g., NADA, OLDA, Oleic acid, NAE) are known to activate TRPV1.112-115 Recently, characterization of biochemistry, phar-macology and other regulatory properties of these endovanilloids have gained momentum. The presence of these molecules, their regulatory enzymes and metabolites have been detected and stud-ied in a variety of tissues.111

However, it has been noted that these endovanilloids are not very specific and are often active on a number of TRP channels. Endovanilloids are subjected to a complex metabolic regulation. The level of endovanilloids in any given tissue is highly variable and are regulated both by their rate of production and degra-dation. Synthesis of endovanilloids can be achieved by different pathways and are mainly regulated by GPCRs and/or several kinases. Recent reports indicate that different metabolites of these compounds can also exert diverse actions on several TRP chan-nels. For example, omega-hydroxylated metabolites of NADA can activate TRPV1.116 However, the identity of all of the endo-vanilloids within a given tissue, their metabolic regulation and their target receptors are not well established. Due to all these factors and lack of sufficient studies, the physiological functions of endovanilloids are highly debatable. In this meeting, Zygmunt et al. demonstrated that 2-AG (2-Arachidonoylglycerol) is a potent TRPV1 agonist as it activates heterologously expressed TRPV1 in whole cell as well as in isolated membrane patches. They propose that the endovanilloids can act as both analgesic and nociceptive molecule depending on the tissue and the pre-vailing conditions. Considering that the endovanilloids are under control of metabolic regulation, these compounds can be use-ful for targeting different TRP channels for clinical purposes. However, in comparison to the usage of exogenous compounds like capsaicin, very little has been done to characterize the endo-vanilliods and more such studies are needed.

Heteromerization of TRP channels. Generally functional TRP channels are homotetramers by their organization. However, it has been suggested that depending on the degree of sequence homology and the expression pattern, some TRP channels can form heteromers as well. Indeed, some studies have demonstrated that different TRP channels can form hetero-tetramers and these heteromers are functional in terms of ionic conductivity.117,118 At present, why and how some TRP channels form heteromers is

insulin-mediated stimulation of TRPM6 current occurred via PI3 kinase and Rac1 signaling.

Parathyroid hormone. It is well known that Parathyroid hor-mone (PTH) acts as a calciotropic hormone and stimulates Ca2+ re-absorption in bone and renal tissue.98,99 However, the precise mechanism by which PTH mediates its actions remains partly unclear. As Ca2+ re-absorption needs involvement of Ca2+ chan-nels, it is speculated that PTH hormones can act on diverse group of Ca2+ channels including some TRP channels. From previous studies it is known that TRPV5 and TRPV6 are expressed in kid-ney and are involved in Ca2+ re-absorption.100 Bindels et al. used calmodulin- and Epac-based FRET sensors and demonstrated that PTH-induced rapid Ca2+-influx in cells that expressed TRPV5.101 The effect of full-length PTH was mimicked by a fragment of PTH (amino acid residues 1–31 of PTH but not 3–31 can activate TRPV5).

However, if PTH affects TRPV5 exclusively or also affects other TRP channels is not clear. In the absence of information about the tissue-wide expression profile of the PTH receptors and other TRP channels, it is difficult to predict if PTH can affect other TRP channels also. However, it appears that TRPV1 is not under the control of PTH, at least in the peripheral neuronal sys-tem. This is due to the fact that in nociceptive myelinated fibers, Parathyroid hormone 2 receptor is present but not in the neurons that express TRPV1.102

Klotho. Klotho is a type I membrane glycoprotein that acts as an anti-aging hormone.103 Extracellular domain of Klotho has two tandem copies of a beta-glucuronidase-like sequence, which can be released as soluble forms after being cleaved by metal-loproteinases such as ADAM10 and ADAM17.103 Bindels et al. demonstrated the role of Klotho in the regulation of TRPV5.104-110 They also found that Klotho is expressed in high amount in kid-ney and co-localizes with TRPV5 (Fig. 3). Moreover, the Ca2+-uptake is more in cells that are positive for TRPV5 and Klotho as compared to the cells that express only TRPV5. Interestingly, sugar residues seem to be important for TRPV5 activation. This is evident by the fact that salicydase, Endo-F or Klotho treatment results in the activation of TRPV5.109,110 Extracellular soluble Klotho induces deglycosylation of TRPV5. By this effect, it not only stimulates TRPV5 but also accumulates more TRPV5 in the plasma membrane. This results in a prolonged expression of TRPV5 at the plasma membrane. However, if and how TRPV5 is involved in the aging process is yet to be explored. Considering

Figure 3. tRpV5 colocalizes with anti-aging hormone Klotho. Shown is the immunehistochemical analysis of Klotho (green) with tRpV5 (red) in mouse kidney sections. these images were kindly provided by prof. R.J. Bindels. For more details see Chang et al.110


keratinocytes by some ill defined mechanism.125,126 Interestingly, the level of melanin expression correlates with the TRPM1 expression in the melanocytes. For example, human melanocytes treated with micro-RNA targeting TRPM1 revealed reduced ratio of melanin with respect to the total protein. Since melanin production is dependent on tyrosinase enzyme, they also checked for the expression level of tyrosinase enzyme in these two differ-ent cell lines. They found that the level of tyrosination is same in these cell lines indicating that the altered level of melanin is due to different level of TRPM1 expression. This work proposes that TRPM1 is an ion channel whose function is critical to nor-mal melanocyte pigmentation. These investigators found that the dark skin has more TRPM1 expression as well as more melanin (with respect to the total protein) as compared to the light skin.

TRPC3 is the “moon walker”. Ester Becker screened some mouse mutants and found a line where the animals display motor as well as coordination defects.127 These animals fail to come back from the end of a static rod and also show loss of cerebellar Purkinje cells. Gene sequencing confirmed that the mutation is in the TRPC3 gene, particularly in exon 7 and cause a T (Thymine) to A (Adenine) mutation. Interestingly, the mutant animal moves backward in the same manner as the pop star Micheal Jackson used to do in his famous dance sequence in moon walker album. That is why the mutant line (Mwk-/-) received its name as “moon walker”. The mutant animal also does not have uniform steps. The locomotive defect of the mutant animals can be explained by the fact that TRPC3 is expressed in Purkunjee cells at around P14 to P21 days, and mutant channel has a “gain of function”, which is toxic in nature. This is evident by the fact that Mwk-/- neurons have defective neurite outgrowth where dendritic branching is severely affected. This mutant line has been considered as a novel mouse model to study the cerebellar ataxia.

TRPM7 and gene regulation. The expression of the TRP channels is mostly tissue- and age-specific, indicating that their expression is highly regulated. Clapham et al. showed that there are other possible ways of regulation, e.g., TRP channels can also regulate the expression of other genes. For example, TRPM7 interacts directly with the DEDAF protein which belongs to “polycomb” group of proteins and thus is involved in the chro-mosomal and transcriptional regulation during development. Interestingly, nuclear localization of DEDAF is reciprocally regulated in the presence of TRPM7, which has a functional kinase at its C-terminal region. Therefore, in case of TRPM7 expression, DEDAF protein stays in the cytoplasm and when there is no expression of TRPM7, the DEDAF localizes to the nucleus.

TR(I)Ps for smoking. There are several molecular factors that determine the liking or disliking for smoking. Previous studies suggest that the nicotinic acetylcholine receptor is the main, if not sole, candidate which recognizes and senses nicotine. However, recent data suggest that several TRP channels can also respond to nicotine.128,129 Interestingly, effect of nicotine on TRP channels seems to be conserved throughout the animal kingdom. Xu et al. show that the TRP1 and TRP2 in C. elegans are involved in the nicotine sensitivity.130 In this regard, Nilius et al. also showed that nicotine directly activates TRPA1.131 While the response

not clear. It is not known if all the TRP channels are able to form heteromers. In this respect, recent studies with the polycystin-1 and polycystin-2 types of TRP channels shed new light on the heteromerization properties of TRP channels.

Ehrlich et al. demonstrated that TRPP2 (also known as poly-cystin-2 or PC2 channel) inhibits the activity of the ryanodine receptor (RyR).119 Interestingly, TRPP2 interacts with RyR via its N-terminal region (amino acid residues 130–220). Using NMR spectroscopy, they demonstrate that the EF-hand regions of PC2 show significant structural change in response to Ca2+, which results in extension of the C-terminal region. This explains why the C-terminal tail of PC2 inhibits the function of RyR in a dose-dependent manner. They also found that PC2 interacts with PKD1 (also known as polycystin 1 or PC1) in 3:1 ratio and forms a complex. Apart from the RyR and PC1, TRPP2 also interacts with TRPC1. According to their proposed model, a coiled-coil domain present in the C-terminus of TRPP2 is criti-cal for the homomeric and heteromeric complex formation. In agreement with this, they demonstrate that mutations that dis-rupt the trimeric coiled coil domain of TRPP2 disrupt the assem-bly of TRPP2 homotrimer and TRPP2-PC1 complex formation. However, the structure proposed by them is different from the structure proposed earlier (Yu et al. abstract # 3) suggesting that more work is needed.120-122

Recent studies from Lambert et al. (abstract # 61) have dem-onstrated that the close homologues like TRPM1 and TRPM3 can form functional heteromeric channel as confirmed by immu-noprecipitation and measurement of the ionic conductance. Interestingly, a study conducted by Yao et al. and Yang et al. demonstrated that heteromultimer formation is possible even when two channels are not closely related. Yao et al. reported that TRPC1 associates with BK (Ca2+) channel123 as well as TRPV4 (Ma et al. abstract # 11) and forms a functional het-eromeric complex. They confirmed these TRPC1 and TRPV4 interactions by fluorescence resonance energy transfer (FRET), co-immunoprecipitation and subcellular localization studies. Similarly, Yang et al. demonstrated that three units of TRPP2 forms functional complex with one unit of PKD1.120 However, at this time, it is difficult to comment if the heteromerization is occurring due to overexpression of the two related or unrelated TRP channels. Whether these TRP channels form heteromers endogenously with low expression level and also in vivo condi-tions remains an open question.

Black and white side of TRPM1. Oancea et al. presented the role of TRPM1 in relation to the pigmentation.124 They have demonstrated that at least 5 isoforms of TRPM1 are expressed in human melanocytes. They found that the expression of TRPM1 is low in the non-invasive mouse melanoma B16-F1 cells while the expression is relatively high in invasive B16-F10 cells. The TRP-current measured from these two cell lines also correlates with the whole cell voltage-clamp experiments, as this current can be reduced by the RNA interference (RNAi) targeting TRPM1 and can be blocked by the La3+ ions.

Final pigmentation of the skin is dependent on the mela-nin content of the keratinocytes. Human melanocytes have “spine-like structures” from where melanosomes migrate to the


Urine imaging is basically done by placing a piece of paper towel at the floor of the animal cage and this paper towel indicates all the places where the animal urinates as these specific areas develop spots. Generally, rodents prefer to urinate at the corners of the cage and very rarely at the middle of the cage. Thus, small spots at the middle of the cage indicate the “out-of-control” stage of the animals. Notably, numerical quantification and statistical analysis of the area of the spots and the number of the spots give good estimation of the “urination status” and/or the “urination mode” of the animals. Using this technique, Nilius et al. have shown that TRPV4 knock out mice (trpv4-/-) urinate often, and also in the middle of the floor, indicating that the animals are mostly in the “out-of-control” stage.

While Ca2+-imaging is expensive and needs high-end setups to characterize the function of TRP ion channels at the cellu-lar level, “urine imaging” is a cheaper, quick and robust method which is applicable to the whole animal. The “urine imaging” could supplement the need of the tedious Ca2+-imaging to a large extent, provided the function of the TRP channel of interest at the cellular level correlates well with the urination behaviors of the animal. Further modification of this method can improve these kinds of studies. For example, applying some chemical/enzymatic indicator on the paper towel can develop some color by reacting with the urine. Thus, both quality and quantity of the urine can be judged accurately and directly from the spot size as well as from the color intensity.

Directions for future research. In this meeting several aspects of TRP channels were discussed from the view point of appli-cation of TRP research for the betterment of human health in general.

TRP channels for better health. TRP channels are directly or indirectly involved in pain, and many other diseases. Their func-tions are essential for normal life.145,146 Identification of new com-pounds that can activate or inhibit respective TRP channels in a given tissue is of paramount importance. Progresses are being made in this area.

For example, TRPM7 knock out animals die in the embry-onic stage and it is involved in ischemia-induced heart and brain-damage. Tymianski et al. have screened more than 60,000 compounds and identified “M6”, a compound that acts as a direct inhibitor of TRPM7. The specificity of this compound is under investigation. If proved to be specific, then this compound may have an important role in the treatment of ischemic cardiac dis-eases, and stroke.147 Similarly, Varben et al. screened more than 200,000 small compounds and found two compounds that can block TRPC6 (Varben et al. abstract # 68). These compounds have good drug-like properties and represent two distinct chemi-cal scaffolds. Interestingly, these two hits do not have any action on TRPC3, TRPV5 or Na

V1.5 and Ikr channels. In this context,

it is noteworthy to mention that Andreev et al. identified a 56 residue length polypeptide (named APHC1) from sea anemone (Heteractis crispa) venom, which inhibits capsaicin induced currents in TRPV1. It produces significant antinociception, inhibits hyperalgesia. Being a polypeptide, it has some advan-tage over small molecules and this polypeptide may be of advan-tage in the behavior treatment of hyperalgesia. AMTB, a novel

to nicotine via the nicotinic acetylcholine receptor is fast, the response to nicotine via the TRPA1 is slow and sustained. These observations may also explain why nicotine patches produce some burning sensation, itching and skin irritation. In addition, Yang et al. predicted that TRPC3 might also be involved in nicotine response (Yang et al. abstract # 73). However, more studies are required in this area.

Activation of TRP channels by gas. TRP channels are spe-cialized for the detection of taste, smell, pain, temperature, hormone and pheromone, and are involved in many behavioral as well as other complex functions including olfaction. In this regard, some recent results show that a number of volatile com-pounds act on TRP channels. In this meeting, Taylor-Clark et al. showed that TRPA1 can be activated by ozone (O

3).132 Similarly,

nitric oxide (NO) can induce nociception in mice via TRPV1 and TRPA1.133 Interestingly, it has been noted that another gas, H

2S can also affect TRP channels. A recent study demonstrates

that NaHS (donor of H2S) can induce Ca2+-influx in TRPA1-

expressing CHO cells, but not in non-transfected cells.134 This result is in line with the fact that many cysteine modifying com-pounds exerts effects on TRP channels.44,135

TRP channels and stem cells. Previous reports also suggest that in vitro expression of TRP channels can alter the cellular morphology as well as function, and may result in cell differ-entiation.136-139 By regulating Ca2+ and other second messengers, the TRP channels may contribute to the survival and differentia-tion of cells and tissues, especially in the early embryonic stages. Indeed, expression of some TRP channels, like TRPV1 in the early embryonic stages has been reported,136,140 and the expres-sion of several TRP channels co-relate with the differentiation of the stem cells.141 Being non-selective Ca2+ channels, TRP chan-nels can regulate the Ca2+-signaling events including Ca2+-waves. These TRP channel-mediated functions are critical for many developmental, neuronal and other functions.142 For example, TRPA1 is known to increase glutamate release from brain stem cells.143 TRPM7 is critical for the survival of bone marrow derived mesenchymal stem cells.144 In this meeting, Valerio et al. pre-sented results which suggest that TRPV2 is expressed in neuro-blastoma cells (abstract # 51). They demonstrated that expression of TRPV2 enhances the expression of astrocytic and neuronal markers like GFAP and β-tubulin III. This function of TRPV2 may be responsible for the development of Glioblasoama, a par-ticularly invasive tumor in many patients. Considering the fact that expression of some TRP channels are cell- and tissue-specific and activation of particular TRP channels can be achieved by specific physical and/or chemical stimuli, combination of TRP channels and their respective ligands have potential to open up new areas of the stem cell engineering. Unfortunately, only a few studies have so far investigated the involvement of the TRP chan-nels in stem cells.

New techniques. This meeting has witnessed the introduction of some novel and innovative techniques that helped characterize the TRP channels. Here we discuss one of these.

“Urine-imaging” as a substitute of “Ca2+-imaging”. Nilius et al. have shown the effect of TRPV4 gene knock out on the urination pattern by using their so called novel “urine imaging” technique.


glass coating, which generally varies depending on commercial sources, may affect the response of a TRP channel in a patch-clamp experiment. This is particularly important as TRP chan-nels are highly sensitive to many compounds and can integrate multiple signaling events. In this regard, concerns have been expressed about the authenticity of the commercially available antibodies. Care must be taken to verify the quality of the com-mercially available antibodies before the results are reported.

Prof. David Clapham proposed to launch a web-site where the quality of the antibodies can be discussed by the actual users. In the wake of this meeting Md. Shahiul Islam’s lab has started developing of a web-site where users can share their experiences on the use of antibodies (not just TRP antibodies) and rate them. An official “TRP channel homepage” is also in the pipe-line.

Until recently, the TRP channel field has been dominated by the electrophysiology and calcium imaging experiments, as the

TRPM8 antagonist might be use-ful for treatment of painful bladder syndrome.148

Development of new generation pesticides. A great hope to control many of the insect-borne disease was raised in this meeting when Montell et al. showed that certain natural compounds have effects on the insect TRP channels but not on TRP channels of higher organ-isms. For example, “citronellal”, a natural compound can activate insect TRPA but not Xenopus TRPA. So, this compound can be effectively used as insect repellents as these compounds can activate only insect TRP channels. Since the sequence of human TRPA1 is different from that of insect TRPA, this compound or its derivatives can be effectively used to develop potent insect repellents and/or effective pesticides.

Concluding Remarks

In spite of major advances made in the field of research involving TRP channels, there remain several con-cerns. The research on TRP chan-nels is highly focused on certain popular TRP families like TRPV and TRPC members (Fig. 4A and B). The use of correct nomencla-ture is also a matter of concern. For example, three different names like VR1, TRPV1 and capsaicin-recep-tor are still being used to describe the same receptor (Fig. 4C). But the biggest concern lies in the reproducibility of the published results. It has been noted that far too many published results are just not reproducible in other labs. This is particularly true about studies that have relied heavily on “specific” antibodies for char-acterization of TRP channels. Thus, there is an urgent need to identify factors that determine apparently poor reproducibility of many published results. One potential area of concern is possible lack of responsibility in the scientific reporting. This may affect the whole TRP-channel community as one irresponsible report-ing may slow down many other good efforts and may cause loss of significant amount of resources which may hinder the future studies.

To overcome this situation, ideally the materials and methods section should be reported with great details so that the published results can be easily reproduced in other labs. For example, it is possible that apparently minor factors like, materials used for

Figure 4. “Capsaicin receptor” alias tRpV1 is still hot. (A) pubMed search reveals that most researchers are still excited by tRpV channels followed by tRpC and other tRp channels. the values show the publications identified by key words that correspond to different tRp channels. (B) Among all six tRpV channels, tRpV1 (appeared 1,749 times) and tRpV3 (appeared only 98 times) represent the most and the least investigated channel. (C) this cartoon reflects that both tRpV1 and VR1 nomenclature are still in use to describe the capsaicin receptor. A key word like “capsaicin receptor” appeared 3,401 times whereas key words like “tRpV1” and “Vanilloid receptor 1” appeared only 1,749 and 1,689 times respectively. thus, investigators are still using different nomenclatures and terminologies to describe the same gene/protein even after a consensus about the nomenclature for the super family of tRp cation channels were reached by “tRp no-menclature Committee” in association with “HUgo gene nomenclature Committee” in 2002.149 the results are based on a pubMed search made on 9th Jan 2010.


Acknowledgements and notes

Funding was obtained from Vetenskapsrådet (The Swedish Research Council), Svenska Läkaresällskapet (The Swedish Society of Medicine), AstraZeneca, AB and National Institute of Health (NINDS), USA. We thank René Bindels for providing a figure. Help from Dr. Upakarasamy Lourderaj, Dr. Nagendra Sharma, Rakesh Majhi and Dr. Abdur Rahaman in the manu-script preparation is appreciated. We also thank all the partici-pants for sharing their results with us. Participation of Chandan Goswami to the meeting was supported by NISER. We regret for not including all the scientific works that has been presented in this meeting due to the space limitation. This report reflects the views of the authors based on their interpretation of the data pre-sented by the participants in this meeting. The authors undertake no formal responsibility for the scientific authenticity/reproduc-ibility of the data described in this report.

focus was very much on the “channel function”. At present, the involvement of diverse TRP channels in different signaling cas-cades as well as in the development of pathological conditions is drawing more attention. In many instances, involvement of TRP channels in pathological conditions cannot be explained only by an altered cation-influx. In fact, a large number of studies indi-cate that indirect roles of TRP channels (functions other than the cation-influx) may be involved in many processes. It has been noted in this meeting that the TRP channel field is now dealing with the atypical and indirect functions of the channels and their regulations, which are likely to be even more complex and more interesting to study. A significant shift has been made towards the use of endogenous ligands rather than exogenous ligands in order to characterize the TRP channels. However, the progresses with respect to the structural aspects and biophysical proper-ties of TRP channels have been slow, and understanding of the conformational changes of the TRP channels is still limited. In future one hopes to see further advancement of TRP channel research in all of these areas.

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