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Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press; 2007.

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TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades.

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Chapter 22TRPV Channels’ Function in Osmo- and Mechanotransduction


Duke University


In signal transduction of metazoan cells, transient receptor potential (TRP) ion channels have been identified to respond to diverse external and internal stimuli, among them osmotic and mechanical stimuli. This chapter summarizes findings on the TRPV subfamily, both its vertebrate and invertebrate members, with a focus on TRPV4. Of the six mammalian TRPV channels, TRPV1, 2, and 4 were demonstrated to function in transduction of osmotic and mechanical stimuli. Invertebrate TRPV channels, five in C. elegans and two in Drosophila, have been shown to play a role in mechanosensation, such as hearing and proprioception in Drosophila and nose touch in C. elegans, and in the response to tonicity in C. elegans. TRPV4 has been found to function in cellular as well as systemic osmotic homeostasis in vertebrates. In a striking example of evolutionary conservation of function, mammalian TRPV4 has been found to rescue mechano- and osmosensory, not olfactory, deficits of the TRPV mutant line osm-9 in C. elegans, despite not more than 25 percent orthology of the respective amino acid sequences.


Within the TRP superfamily of ion channels [21], the TRPV subfamily came into existence and immediately gained public notoriety in 1997 [14,19], when its founding members, TRPV1 in mammals and OSM-9 in C. elegans, were first reported. TRPV1 was identified by an expression cloning strategy [14]. OSM-9 was identified through genetic screening for worms’ defects in osmotic avoidance [19]. TRPV2, -V3, and -V4 were identified by a candidate gene approach, respectively [13,36,43,56,60,63,74,76]. The latter strategy also led to the identification of four additional C. elegans ocr genes [66] and two Drosophila trpv genes, Nanchung (NAN) and Inactive (IAV) [28,38]. The TRPV channels can be subgrouped into four branches by sequence comparison. One branch includes four members of mammalian TRPVs (TRPV1, -V2, -V3, and -V4); in vitro whole-cell recording showed that they respond to temperatures higher than 42, 52, 31, and 27°C, respectively, suggesting that they are involved in thermosensation, hence the term “thermoTRPs” (reviewed in references 10, 12, 18, 55, and 69, and many other meritorious papers). One invertebrate branch includes C. elegans OSM-9 and Drosophila IAV; the other branch is composed of OCR-1 to -4 in C. elegans and Drosophila NAN.

This chapter focuses on the role of mammalian (in the first place) and also invertebrate (C. elegans) TRPV channels in signal transduction in response to osmotic and mechanical stimuli, in particular on TRPV4. These osmo- and mecha-noTRPs [45] are TRPV1, -2, -4, OSM-9, OCR-2, NAN, and IAV. Other TRPV channels might join this functional group within the TRP superfamily, which certainly also contains non-TRPV channels such as TRPA1 [20,52] or NompC [72]. The following issues are addressed in this chapter. Do TRPV ion channels function in sensing and transduction of osmotic and mechanical stimuli? Which molecular mechanisms are at play? Are the responses to either stimulus linked, possibly via transduction of membrane tension? When answering these questions, one has to bear in mind that (1) the field of TRPV ion channels is young (less than a decade) [14,19] and that (2) the methodological arsenal to answer the above questions for TRPVs has its limitations.


Before the TRPV osmo- and mechanoTRPs receive further consideration, here is a short discourse regarding limitations of heterologous cellular expression systems, which have helped elucidate TRP channels’ function, yet the following qualifiers will have to be realized.

For the field of ion channel physiology, heterologous cellular expression systems have allowed particularly rewarding studies for voltage-gated channels and also for ligand-gated channels such as the nicotinic acetylcholine-receptor, GABA-ergic channels, and NMDA receptors. It is perhaps slightly underappreciated that this concept cannot be transferred seamlessly to the investigation of channels that respond to osmotic and mechanical stimuli. Nonspecific effects may be caused by purely physical effects of these stimuli on the cells, for example, mechanical stimulation. First, a latency has to be determined in order to be able to differentiate direct mechanical activation of the channel (i.e., mechanotransduction happens only by activation of the channel without other signaling molecules directly involved in this signaling) versus an indirect activation (i.e., mechanotransductory channel activation downstream). For a direct response, a latency shorter than one millisecond is required [33–35]. With currently available technology, this means that only patch-clamp recordings satisfy this need. One problem is how to apply the mechanical stimulus without disturbing the recording. With respect to tonicity, the precise beginning of the osmotic stimulus cannot be determined. When applying the osmotic stimulus by streaming bath solution, one has to realize that a mechanical stimulus is coapplied, namely flow, which will affect the cell by exerting shear stress. Also, osmotic and mechanical stimuli as activators of channels are distinctly different from specific activators/ligands (e.g., GABA, NMDA). Most cells will harbor an innate response to primal biophysical stimuli such as tonicity and touch. This means that heterologously expressing a certain ion channel in this context is supplementing a preexisting signaling apparatus by one more molecule. It is quite obvious, on the other hand, that the situation is different for, for example, the response of an epithelial cell or fibroblast to a nervous system–specific ligand/activator such as GABA, glycine, or NMDA.


In heterologous cellular expression systems, there have not been reports on mechanotransduction by TRPV1. Genetically engineered trpv1−/− mice, which have previously been shown to be devoid of thermal hyperalgesia following inflammation [11,23], also displayed an altered response of their bladders to stretching [9]. TRPV1 could be localized to sensory and autonomous ganglia neurons and also to urethelial cells lining the pyelon, ureter, and bladder. When bladder and urothel epithelial cells were maintained in primary tissue cultures, their responses to mechanical stretch were significantly different from wild-type cultures. Specifically, TRPV1+ bladders secreted ATP upon mechanical stretch, which, in turn, is known to activate nerve fibers in the bladder submucosa. This response to mechanical stimulation was greatly reduced in bladders excised from trpv1−/− mice. It appears likely that this mechanism, operative in mice, also plays a role in human bladder epithelia. Intravesical installation of TRPV1 activators is used to treat hyperactive bladder syndromes in spinal cord disease, although the exact effect and mechanism of action of TRPV1 agonists is not clear [4,26,40,62]. Another instance of an altered response to mechanical stimuli in trpv1−/− mice relates to the response of the jejunum to mechanical stretch [58]. Afferent jejunal nerve fibers were found to respond with decreased frequency of discharge in trpv1−/− mice than in wild-type mice [22]. In humans, TRPV1 positive nerve fibers in the rectum were significantly increased in patients suffering from fecal urgency, a pathologic rectal hypersensitivity in response to mechanical distension [16]. Expression of TRPV1+ nerve fibers in rectal biopsy samples from these patients correlated with a lower threshold to mechanical stretch; in addition, the occurrence of TRPV1+ fibers was also correlated with a dysaesthesia of a burning quality. Another recent study focused on possible mechanisms of signal transduction in response to mechanical stimuli in blood vessels [59]. Elevation of intraluminal mechanical pressure in mesenterial arteries was reported to be associated with generation of 20-hydroxyeicosatetraenoic acid, which, in turn, activated TRPV1 on C-fibers leading to nerve depolarization and vasoactive neuropeptide release. With respect to nociception, using trpv1−/− mice, trpv1 was shown to be involved in inflammatory thermal hyperalgesia, but not in inflammatory mechanical hyperalgesia [10,32]. However, a specific and potent blocker of TRPV1 was found to reduce mechanical hyperalgesia in rats [22,57]. These latter results appear in contrast to the lack of difference between trpv1−/− and wild-type mice. Either this discrepancy is due to a species difference between mice and rats pertaining to signal transduction by TRPV1 in inflammation-induced mechanical hyperalgesia, or it may be due to the different mechanisms that affect signaling in a trpv1 general knockout (with likely compensatory gene regulation) versus a specific temporal pharmacological blocking of the TRPV1 ion channel protein that most likely participates in a signaling multiplex. Very recently, reporting a spectacular finding, Sharif Naeini et al. reported that trpv1−/− mice failed to express an N-terminal variant of the trpv1 gene in magnocellular neurons of the supraoptic and paraventricular nucleus of the hypothalamus [51]. These neurons are known to secrete vasopressin, and the trpv1−/− mice were found to have a profound impairment of ADH secretion in response to systemic hypertonic stimuli, and their magnocellular neurons did not show an appropriate electrical response to hypertonicity. Bourque and colleagues [51] conclude that this trpv1 N-terminal variant, which could not be identified at the molecular level, is likely involved as (part of) a tonicity sensor of intrinsically osmosensitive magnocellular neurons. Moreover, Ciura and Bourque [81] report that this splice variant is also expressed in the osmotically sensitive circumventricular organ OVLT, and that OVLT-dissociated neurons from the trpv1−/− mice are defective in their response to hypertonic stimuli.


With respect to the TRPV2 ion channel, we are still awaiting the report on an eventual phenotype of trpv2−/− mice. In heterologous cellular systems, TRPV2 was initially described as a temperature-gated ionotropic receptor for stimuli >52°C [13]. Recently, TRPV2 was also shown to respond to hypotonicity and mechanical stimulation [49]. Arterial smooth muscle cells from various arteries expressed TRPV2. These myocytes responded to hypotonic stimulation with calcium influx. This activation could be diminished by specific downregulation of TRPV2 protein by an antisense strategy. Heterologously expressed TRPV2 in CHO cells displayed a similar response to hypotonicity. These cells were also subjected to stretch by applying negative pressure to the patch pipette and by stretching the cell membrane on a mechanical stimulator. Both maneuvers led to Ca2+ influx that depended on heterologous TRPV2 expression.

TRPV3 has not (yet) been characterized as an osmo- and mechanoTRP, either in heterologous systems or in live animals or human studies. The same is true for TRPV5 and TRPV6.


CHO cells responded to hypotonic solution when they were (stably) transfected with TRPV4 [43]. HEK293 T cells, when maintained by the same authors, were found to express trpv4 cDNA, which was cloned from these cells (genbank AF263523). However, trpv4 cDNA was not found in other batches of HEK293 T cells, so that this cell line was used as a heterologous expression vehicle by other groups [63,74]. When comparing the two settings, it was obvious that the single-channel conductance was not at all similar [43,63]. This perhaps underscores the relevance of gene expression in heterologous cellular systems for the functioning of TRPV4 in response to a basic biophysical stimulus. Also, the sensitivity of TRPV4 could be tuned by warming of the media. Peak sensitivity of gating in response to hypotonicity was recorded at core body temperature of the respective organism, and TRPV4 channels from both birds (core body temp. 40°C) and mammals (37°C) were compared, again in CHO cells [43]. Similar results were found in another investigation with expression of mammalian TRPV4 in HEK293 T cells [27]. In this investigation, the cells were mechanically stretched at isotonicity. At room temperature, there was no response upon mechanical stretch; however, at 37°C the isotonic response to stretch resulted in a very strong calcium influx. In two other investigations, TRPV4 was found to be responsive to changes in temperature [31,73]. Temperature change was accomplished by heating the streaming bath solution (see above comments on flow as a mechanical stimulus). Gating was augmented when hypotonic solution was used as a streaming bath. In one investigation, temperature stimulation could not activate the TRPV4 channel in cell-detached inside-out patches [73]. With respect to the gating mechanism of TRPV4 in response to hypotonicity, two recent papers report conflicting results on phosphorylation sites of TRPV4 that are necessary for the response to hypotonicity.

One paper reported that TRPV4 was tyrosine-phosphorylated in HEK293 T cells and in distal convoluted tubule cells from mouse kidneys [65,77]. Tyrosine phosphorylation was sensitive to specific inhibition of the Src family tyrosine kinases. The Lyn tyrosine kinase was found to coimmunoprecipitate with TRPV4 and to feature a critical role in phosphorylation of TRPV4 (Y253). A point mutation of Y253 reduced hypotonicity-induced gating. On the other hand, in another investigation, in HEK293 T cells, hypotonicity activated TRPV4 by phospholipase-A2–mediated formation of arachidonic acid via a cytochrome P450 epoxygenase pathway [71]. In HEK cells, this signaling mechanism did not apply for TRPV4 gating by increased temperature or by the nonphosphorylating phorbol ester 4-alpha PDD. This latter activation mechanism was reported to depend on phosphorylation of Y555. However, the authors of this study could not replicate the aforementioned finding of tyrosine kinase phosphorylation of Y253 of TRPV4 as critical for hypotonicity-induced gating. Why this discrepancy? It reiterates the pivotal role of the host cell in heterologous expression experiments.

In another recent paper, the ciliary beat frequency of ciliated cells was shown to be influenced by TRPV4 gating [3]. In primary ciliated cells, and also in heterologously transfected HeLa cells, TRPV4 could be activated (mechanically) by exposing the cells to hyperviscous, isotonic media.

Another recent focus in the field of TRP ion channels is intracellular trafficking, posttranslational modification, and subsequent functional modulation. For TRPV4, it was found in heterologous cells (HEK293T) that N-glycosylation between the fifth transmembrane domain and pore loop (position 651) decreases osmotic activation via decreased plasma membrane insertion [75]. Interestingly, N-glycosylation between the first and second transmembrane domains appears to have the same effect on TRPV5, and the anti-aging hormone klotho functions as beta-glucuronidase and subsequently activates TRPV5 [17]. In the kidney (and via systemic klotho possibly elsewhere), klotho could have a similar effect on TRPV4 and function as an amplifier of tonicity-mediated signaling.

TRPV4 also has played a role in maintaining cellular osmotic homeostasis. One particular cellular defense mechanism of cellular osmotic homeostasis is regulatory volume change, namely regulatory volume decrease (RVD) in response to hypotonicity and regulatory volume increase (RVI) in response to hypertonicity. In a recent paper, Bereiter-Hahn’s group reported that CHO tissue culture cells have a poor RVD, which, after transfection with TRPV4, improves in a striking manner [8]. In another study, Valverde’s group published that TRPV4 mediates cell swelling–induced Ca2+ influx into bronchial epithelial cells that triggers RVD via Ca2+-dependent potassium channels [6]. This cell-swelling response was not operational in cystic fibrosis (CFTR) bronchial epithelia, where, on the other hand, TRPV4 could be activated by 4-alpha-PDD, leading to Ca2+ influx. Thus, in CFTR bronchial epithelia, RVD could not be elicited by hypotonicity but by 4-alpha-PDD. In yet another investigation, Ambudkar and colleagues found a concerted interaction of aquaporin-5 (AQP-5) with TRPV4 in hypotonic swelling–induced RVD of salivary gland epithelia [42]. These exciting findings elucidate mechanisms that maintain function of secretory epithelia (such as salivary, tear, sweat, airway, and intestinal glands) that underlie watery secretion based on a concerted interaction of TRPV4 with AQP-5 (for another investigation pertaining to this topic see reference 82).

In trpv4−/− mice, the response to noxious mechanical stimulation is diminished [44,64]. In the absence of TRPV4, the threshold to noxious mechanical stimulation was significantly elevated. This result was obtained using two standard tests, the Randall-Sellito test, which applies mechanical pressure by squeezing the paw, and an automatized von Frey test, which applies mechanical stimulation from underneath the hindpaw, leading to withdrawal [44]. In mice, paw withdrawal in response to a noxious temperature was not different between trpv4−/− mice and wild-type mice [44,64]. However, a more detailed testing of abnormalities in response to thermal stimuli revealed an abnormal inflammatory hyperalgesia in trpv4−/− mice and an altered behavior in a thermal gradient [41,68]. When rats were sensitized with taxol, their sensitivity to noxious mechanical stimuli was strikingly lowered as a result of the taxol-induced neuropathy [24,25]. When these rats were treated intrathecally with TRPV4-specific antisense oligonucleotides, taxol-induced mechanical hypersensitivity was eliminated [1]. This clearly suggests a role for TRPV4 in mediating hyperalgesia in response to mechanical stimuli in an animal model for neuropathic pain. Last, but not least, with respect to mechanotransduction in trpv4−/− mice, they do not show signs of inner ear dysfunction including deafness [44], which has to be viewed against the expression pattern of trpv4 in the inner ear [43,50]. trpv4 mRNA could be demonstrated in the secretory epithelia of the stria vascularis/ tegmentum vasculare and in neurosensory inner ear hair cells of both rodents and birds. This negative finding in vivo does not exclude, however, a role for TRPV4 in inner ear function.

trpv4−/− mice, when stressed with systemic hypertonicity, did not counterregulate their systemic tonicity as efficiently as wild-type littermates [44]. Their drinking was reduced, and systemic tonicity was significantly higher. Continuous infusion of the ADH analogue dDAVP led to systemic hypotonicity, whereas renal water read-sorption capacity was not altered between genotypes. Antidiuretic hormone synthesis in response to osmotic stimulation was reduced in trpv4−/− mice. Hypertonic stress led to reduced expression of c-FOS+ cells in the sensory circumventricular organ, OVLT, indicative of impaired osmotic activation. These findings in trpv4−/− mice point toward a deficit of osmotic sensing in the central nervous system. Thus, TRPV4 is necessary for maintaining systemic osmotic equilibrium in mammals. It is conceivable that TRPV4 acts as an osmotic sensor in the CNS. The impaired osmotic regulation in trpv4−/− mice reported in the author’s paper differs from that published in another report. While our experiments showed that trpv4−/− mice secrete lower amounts of ADH in response to hypertonic stimuli, the results from Mizuno et al. [48] suggest that there is an increased ADH response to water deprivation and subsequent systemic administration of propylene glycol. The reasons for this discrepancy are not obvious. In our study, a blunted ADH response and diminished cFOS response in the OVLT in trpv4−/− mice upon systemic hypertonicity suggest, as one possibility, an activation of TRPV4+ sensory cells in the OVLT by hypertonicity. This consideration, in contradiction with results from heterologous expression systems, is important and will be extended below. However, together with the above findings of the Bourque group on abnormal osmotic regulation in trpv1−/− mice, the fascinating possibility is that TRP(V) channels might interact to form critical transduction multiplex in the regulation of systemic tonicity. In other words, is Verney’s osmoreceptor made up of heteromers derived from the trpv1/4 genes?

In a recent publication, Alessandri-Haber et al. demonstrate that hypertonic subcutaneous solution leads to pain-related behavior in wild-type mice, which is not present in trpv4−/− mice [2]. When sensitizing nociceptors with prostaglandin E2, the pain-related responses to hypertonic stimulation became more frequent and were greatly reduced in trpv4−/− mice. These in vivo data could not be recapitulated in acutely dissociated DRG neurons upon stimulation with hypertonicity and subsequent calcium imaging; there was a discernible rise in intracellular calcium, yet genotypes did not differ. As for hypotonic stimulation, this did not elicit pain-related behavior in mice, which could only be evoked after presensitization with PGE2. And again, this behavior was strikingly reduced in the absence of trpv4. Contrary to hypertonicity, hypotonicity led to an increase of intracellular calcium in primary DRG neurons, yet intracellular calcium was significantly reduced in the absence of TRPV4. Taken together, this investigation indicates differences in the response of mice to noxious tonicity stimuli depending on the presence or absence of TRPV4. Yet at the level of a critical transducer cell, namely the DRG sensory neuron in acutely dissociated culture, only hypotonicity led to a rise of intracellular calcium that depended on the presence of TRPV4. Perhaps other closely associated cells, such as epidermal keratinocytes or Schwann cells, assume a critical role in the transduction of hypertonic noxious stimuli or, as a nonmutually exclusive possibility, the in vivo situs where the sensory neuron extends a process that measures several hundred or thousand times the diameter of the soma, is not reflected faithfully by the reductionist model of the primary cultured DRG neuron.


Cloning of the osm-9 Gene, a Founding Member of the trpv Gene Family

As mentioned in the introduction, the osm-9 mutant was first reported in 1997 [19]. The forwards genetics screen in C. elegans consisted of a confinement assay with a high-molar osmotically active substance. osm-9 mutants did not respect this barrier, and the mutated gene was found to be a TRP channel. On closer analysis, osm-9 mutants did not respond to aversive tonicity stimuli, they did not respond to mechanical tapping of their “noses,” and they did not respond to (aversive) odorants. The OSM-9 channel protein was expressed in amphid sensory neurons, the worms’ cellular substrate of exteroceptive sensing of noxious chemical, osmotic, and mechanical stimuli. The OSM-9 channel was expressed in the sensory cilia of the AWC and ASH amphid sensory neurons. Bilateral laser ablation of the ASH neuron has led to a deficit in avoidance of noxious osmotic, nose touch, and olfactory stimuli [37], hence the term “nociceptive” neuron [7]. The OSM-9 protein could not, however, be expressed in heterologous cellular expression systems, and explant cultures of amphid sensory neurons were not viable.

Next, also by the Bargmann laboratory, four additional TRPV channels from C. elegans were cloned, named OCR-1 to -4 [66]. Of these four channels, only the OCR-2 channel was expressed in ASH. The ocr-2 mutant phenotype was virtually identical to the osm-9 phenotype with respect to worm “nociception,” and there was genetic evidence that the two channels interacted. When expressing the mammalian capsaicin receptor TRPV1 in the ASH sensory neurons, neither osm-9 nor ocr-2 mutants could be rescued for any of their deficits, but osm-9 ash::trpv1 transgenic worms displayed a strong avoidance response to capsaicin, which normal worms virtually do not show.

TRPV4 Expression in ASH Rescues osm-9 Mechanical and Osmotic Deficits

Next, TRPV4 was transgenically targeted to ASH of osm-9 mutants. Surprisingly, this rescued osm-9 mutants’ defects in avoidance of hyperosmotic noxious stimuli and nose touch [46], not odorant avoidance of osm-9, suggesting that this specific function of TRPV channels differs between vertebrates and invertebrates. This basic finding of the rescue experiments in osm-9 ash::trpv4 worms has implications for mechanisms of signal transduction in the ASH neuron (see Figure 22.1).

FIGURE 22.1. (From reference ) Schematic representations illustrating how signal transduction in sensory (nerve) cells in response to odorant (A), osmotic (B) and mechanical (C) stimuli could possibly function.


(From reference ) Schematic representations illustrating how signal transduction in sensory (nerve) cells in response to odorant (A), osmotic (B) and mechanical (C) stimuli could possibly function. (A) The odorant activates the TRPV ion channel via a (more...)

TRPV4 appeared to be integrated into the normal ASH sensory neuron signaling apparatus, because the transgene failed to rescue these deficits in other C. elegans mutants defective in osmosensation and mechanosensation (including OCR-2, bespeaking the specificity of the observed response). A point mutation in the pore loop of TRPV4, M680K, virtually eliminated rescue, indicating that TRPV4 functions as an ion channel. In an attempt to recapitulate the properties of the mammalian channel in the nociceptive behavior of the worm, it was found that the sensitivity for osmotic stimuli and the effect of temperature on the avoidance responses of osm-9 ash::trpv4 worms more closely resembled properties of mammalian TRPV4 than that of normal worms. These data suggest that TRPV4 functions as an osmotically and mechanically gated channel, and that, in this model, TRPV4 directs the osmotic and mechanical avoidance behavior of the worm. TRPV4 does not rescue the odorant avoidance deficit of osm-9 mutant worms, where G-protein-coupled receptors function as odorant sensors, and TRPV4 did not function downstream of other known mutations that affect nose touch and osmotic avoidance. In aggregate, these findings and considerations suggest that mammalian TRPV4 functioned as a component of the osmotic and mechanical sensor. TRPV4 was de facto expressed only in ASH, a single sensory neuron, where the mammalian protein, with a similarity to OSM-9 of approximately 25 percent, was trafficked correctly to the ASH sensory cilia, a distance of about 50–100 micrometers! The rescue was specific (not for OCR-2, not by mammalian TRPV1), and it respected genetically defined boundaries for osmotic and nose-touch avoidance. On the other hand, this study leads to stimulating questions. Whereas TRPV4 restores responsiveness to hyperosmotic stimuli in C. elegans osm-9 mutants, it is only gated by hypoosmotic stimuli in transfected mammalian cells. The reasons for this are not understood. One possibility is suggested by the results of a study where a mechanosensitive ion channel, gramicidin A, behaved either as a stretch-inactivated or as a stretch-activated channel depending on the lipid composition of the surrounding lipid bilayer [47]. An alternate possibility is that TRPV4 forms heteromultimeric complexes with other proteins, as was recently shown for the MEC proteins, and that this multiplex has different properties [15,29]. TRP ion channels are known to form heteromeric complexes with related family members [78,79]. OCR-2 and OSM-9 are the only C. elegans TRPV family members that are expressed in ASH neurons, and OCR-2 expression is essential for TRPV4 to rescue the sensory defects of osm-9 worms [47,66,67]. Related to this study, it was recently reported that TRPV2 could rescue one particular deficit of the ocr-2 mutant, namely the dramatic downregulation of serotonin biosynthesis in the sensory ADF neuron, but mammalian TRPV2, unlike TRPV4 directing behavior in osm-9, did not complement the osmotic avoidance reaction that was lacking in ocr-2 mutants [61,80]. Common to these investigations is the conservation of TRPV signaling across phyla that were separated by several hundred million years of molecular evolution, and this in view of low sequence homology!

In reference to the Drosophila TRPV channels, NAN and IAV, the reader is directed to original papers [28,38] and reviews [45,70]. One interesting generalization appears to be that a null mutant in an invertebrate TRPV channel has a stronger phenotype than a mutation in a mammalian TRPV channel.


Apart from the unexpected turns (the inevitability of those to occur renders the blossoming field of TRP channels even more appealing than it already is [53,54]), the obvious topic for the (near) future is the investigation of the functional significance of protein–protein interactions of TRP(V) ion channels with known and to-be-discovered interaction partners. For example, a very interesting example of protein–protein interactions of TRPV4 splice variants from airway epithelia was reported [5], highlighting the need to also study the complexity of trp genes and their variants. In addition, there is the obvious potential for TRP channels as targets for therapy [30,39].


The author was supported by a K08 Career Development Award of the National Institutes of Mental Health, by funding from the Whitehall Foundation (Palm Springs, FL), American Federation for Aging Research (New York, NY), the Klingenstein Fund (New York, NY), and Duke University (Durham, NC).


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