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Symposium Reports |
1 Duke University, Center for Translational Neuroscience, Durham, NC 27710, USA
Abstract
In signal transduction of metazoan cells, ion channels of the family of transient receptor potential (TRP) have been identified to respond to diverse external and internal stimuli, amongst them osmotic stimuli. This report highlights findings pertaining to the TRPV subfamily, focusing on mammalian members. Of the six mammalian TRPV channels, TRPV1, 2 and 4 were demonstrated to function in transduction of osmotic stimuli. TRPV channels have been found to function in cellular as well as systemic osmotic homeostasis. In a striking example of evolutionary conservation of function, mammalian TRPV4 has been found to rescue osmosensory deficits of the TRPV mutant strain osm-9 in Caenorhabditis elegans, despite not more than 26% orthology of the respective proteins.
(Received 15 December 2006;
accepted after revision 7 March 2007; first published online 14 March 2007)
Corresponding author W. Liedtke: Duke University, Center for Translational Neuroscience, Durham, NC 27710, USA. Email: wolfgang{at}neuro.duke.edu
Response to osmotic stimuli: a function of TRPV ion channels, apparent since ‘birth’ of this subfamily
Within the transient receptor potential (TRP) superfamily of ion channels (Cosens & Manning, 1969; Montell & Rubin, 1989; Wong et al. 1989; Hardie & Minke, 1992; Zhu et al. 1995), the TRPV subfamily stepped into the spotlight in 1997 (Caterina et al. 1997; Colbert et al. 1997). The spectacular find of the capsaicin receptor TRPV1 led to subsequent research in the direction of study of responses to ligand (capsaicin), acidity and thermal stimuli. Slightly less attention was perhaps dedicated to the other founding member, the Caenorhabditis elegans osm-9 gene. The discovery of osm-9 carried with it the suggestion that TRP channels might subserve critical roles in transduction of osmotic and mechanical stimuli. Subsequently, TRPV2, 3 and 4 were identified by a candidate gene approach (Caterina et al. 1999; Kanzaki et al. 1999; Liedtke et al. 2000; Strotmann et al. 2000; Wissenbach et al. 2000; Peier et al. 2002; Smith et al. 2002; Xu et al. 2002). When heterologous expression-system electrophysiology data were available for TRPVs, their non-selective conductance of cations, with a preference for Ca2+, was apparent.
This review provides focused comment on ‘osmo- and mechano-TRPs’ (Liedtke & Kim, 2005), which comprises, of the TRPV subfamily, up to now, TRPV1, 2 and 4, OSM-9, OCR-2, NAN and IAV (Fig. 1).
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In heterologous cellular expression systems, there were no reports on transduction of osmotic stimuli involving TRPV1. Genetically engineered trpv1–/– mice, which have previously been shown to lack thermal hyperalgesia following inflammation (Caterina et al. 2000; Davis et al. 2000), also showed an altered response of their magnocellular hypothalamic neurones to tonicity stimuli. Very recently, Naeini from Bourque's group reported that trpv1–/– mice failed to express an N-terminal variant of the trpv1 gene in magnocellular neurones of the supraoptic and paraventricular nucleus of the hypothalamus (Naeini et al. 2005). Since these neurones are known to secrete vasopressin, the trpv1–/– mice were found to have a profound impairment of arginine-vasopressin (AVP) secretion in response to systemic hypertonicity, and their magnocellular neurones did not show an appropriate bioelectrical response to hypertonicity. These findings led to the conclusion that this trpv1 N-terminal variant, unidentified at the molecular level, is probably involved as a tonicity sensor of intrinsically osmosensitive magnocellular neurones. In another paper published recently, Ciura & Bourque (2006) reported that neurones within the organum vasculosum laminae terminalis (OVLT), a sensory circumventricular organ in the brain, lacking a blood–brain barrier, also express an N-terminal trpv1 variant, and that their osmotic sensing in the absence of trpv1 was critically impaired.
The bladder of trpv1–/– mice also showed an abnormal response to stretch (Birder et al. 2002). TRPV1 could be localized to sensory and autonomous ganglia neurones innervating the bladder, and to urethelial cells. When bladder urothel-epithelial cells were cultured, their response to mechanical stretch and hypotonicity was different from wild type. Specifically, the trpv1+/+ bladders secreted ATP upon stretch and hypotonicity. This response to mechanical stimulation was greatly reduced in trpv1–/– bladders. It appears likely that this mechanism, functional in mice, also plays a role in human bladder. Intravesical instillation of TRPV1-activators is used to treat hyperactive bladder in spinal cord disease (Dinis et al. 2004).
Another instance of an altered response to mechanical stimuli in trpv1–/– mice relates to the stretch response of the jejunum (Rong et al. 2004). Afferent jejunal nerve fibres were found to respond with decreased frequency of discharge in trpv1–/–compared with wild-type mice. In humans, in the rectum, TRPV1-positive fibres were found to be significantly increased in patients suffering from faecal urgency, a condition with rectal hypersensitivity in response to mechanical distension (Chan et al. 2003), in addition to mechanically hypersensitive haemorrhoid tissue (di Mola et al. 2006). Expression of TRPV1-positive fibres in rectal biopsy samples from faecal-urgency patients was positively correlated with a decreased mechanical threshold.
Another recent study focused on possible mechanisms of signal transduction in response to mechanical stimuli in blood vessels (Scotland et al. 2004). Elevation of luminal pressure in mesenteric arteries was shown to be associated with generation of 20-hydroxyeicosatetraenoic acid, which activated TRPV1 expressed on C fibres, leading to depolarization and vasoactive neuropeptide release. With respect to nociception, using trpv1–/– mice, trpv1 was shown to be involved in inflammatory thermal hyperalgesia, but not inflammatory mechanical hyperalgesia (Caterina et al. 1999; Gunthorpe et al. 2002). However, a specific blocker of TRPV1 was found to reduce mechanical hyperalgesia in rats (Pomonis et al. 2003). These latter results appear contradictory. Either this discrepancy results from a species difference between mice and rats, or it may result from different mechanisms that affect signalling in a trpv1 pan-knockout mouse versus a specific temporal pharmacological blockade of TRPV1 ion channel proteins, which very probably participate in multiplex protein complexes.
Taken together, loss-of-function studies using trpv1–/– mice clearly imply that trpv1 plays a significant role in transduction of osmotic and mechanical stimuli. Despite this phenotypical clarity, further details and the molecular mechanism await further investigation.
Role of trpv2 in osmo-mechanotransduction
In heterologous cellular expression systems, TRPV2 was initially described as a temperature-gated channel for stimuli > 52°C (Caterina et al. 1999). Recently, TRPV2 was also demonstrated to respond to hypotonicity and mechanical stimuli (Muraki et al. 2003). Arterial smooth muscle cells expressed TRPV2. These myocytes responded to hypotonicity with Ca2+ influx. This activation could be reduced by specific downregulation of TRPV2 by an antisense method. Heterologously expressed TRPV2 in chinese hamster ovary permanent cell line (CHO) cells displayed a similar response to hypotonicity. These cells were also subjected to stretch by suction of the recording pipette and by stretching the cell membrane on a mechanical stimulator. Both manoeuvres led to Ca2+ influx that was dependent on heterologous TRPV2 expression.
In aggregate, having been discovered as a ‘thermo-TRP’, TRPV2 appears to be an ‘osmo-mechano-TRP’ as well.
Role of TRPV4 in osmo-transduction and hydromineral homeostasis
TRPV4-transfected CHO tissue culture cells responded to hypotonic solution (Liedtke et al. 2000). HEK 293T cells, when maintained by the same authors, were found to express trpv4 cDNA, which was cloned from these cells. However, trpv4 cDNA was not found in other batches of HEK 293T cells, so that this cell line was used for heterologous expression by others (Strotmann et al. 2000; Wissenbach et al. 2000). Notably, when comparing the two settings it was obvious that the single-channel conductance of TRPV4 was different (Liedtke et al. 2000; Strotmann et al. 2000). This underscores the relevance of complimentary gene expression in heterologous cellular systems for the functioning of TRPV4 in response to a basic biophysical stimulation. Also, it was found that the sensitivity of TRPV4 could be modulated by warming of the media. Similar results were found in another investigation when expressing TRPV4 in HEK 293T cells (Gao et al. 2003). In addition, in this investigation, the cells were mechanically stretched (at isotonicity). At room temperature, there was no response to mechanical stress, but at 37°C the response to stretch resulted in the maximal Ca2+ influx of all conditions. In two other investigations, heterologously expressed TRPV4 was found to be responsive to changes in temperature (Guler et al. 2002; Watanabe et al. 2002). Temperature change was accomplished by heating the streaming bath solution. This particular method of application of a temperature stimulus represents a mechanical stimulus per se because the streaming bath solution exerts a mechanical stress (flow). Gating of TRPV4 was found to be amplified when hypotonic solution was used as the streaming bath. In one investigation, temperature stimuli could not activate the TRPV4 channel in cell-detached inside-out patches (Watanabe et al. 2002).
In regard to maintenance of systemic osmotic pressure in live animals, trpv4–/– mice, when stressed with systemic hypertonicity, did not regulate their systemic tonicity as efficiently as wild-type mice (Liedtke & Friedman 2003). Their drinking, both spontaneous and in response to intraperitoneal application of hypertonic saline, was reduced, and systemic tonicity was significantly elevated. Continuous infusion of the AVP analogue desmopressin (dDAVP) led to systemic hypotonicity, whereas renal water reabsorption was not changed in either genotype. Antidiuretic hormone secretion in response to osmotic stimulation was reduced in trpv4–/– mice. Hypertonic stress led to reduced expression of the immediate-early transcription factor c-FOS in the nuclei of cells located in the circumventricular organ OVLT, indicating an impaired osmotic activation. These findings in trpv4–/– mice point towards a deficit in central osmotic sensing. Thus, TRPV4 is necessary for the maintenance of the tonicity equilibrium in mammals. It is conceivable that TRPV4 acts as an osmotic sensor in the CNS. The reported impairment of osmotic regulation in trpv4–/– mice differs from that published in another paper. While the author's experiments showed that trpv4–/– mice secrete lower amounts of AVP in response to hypertonic stimuli, the results from Mizuno et al. (2003) suggest that there is an increased AVP response to water deprivation and subsequent systemic administration of propylene glycol, which they also observed in an organotypic preparation of the hypothalamus. The reasons for this difference are not obvious, but the different nature of the stimuli in vivo has to be taken into account, namely intraperitoneal application of hypertonic saline versus fluid deprivation compounded by subcutaneous injection of polyethylene glycol, which leads to a sequestration of volume. In the author's investigation, a blunted AVP response and diminished c-FOS response in the OVLT of trpv4–/– mice upon systemic hypertonicity suggests, as one possibility, an activation of TRPV4-positive sensory cells in the OVLT by hypertonicity.
In another recent investigation, rats were infused intracerebroventricularly with 4-
-PDD, a non-phosphorylating phorbol ester that has been shown previously to activate TRPV4 (Tsushima & Mori, 2006). This manoeuvre led to inhibition of water-intake behaviour. It also blocked the dipsogenic effects of intracerebroventricular angiotensin II. Dipsogenic osmotic stimuli were not influenced in their effect; locomotor activity was significantly downregulated. No change in body temperature was noted.
In aggregate, the trpv4 gene functions critically in regulation of systemic tonicity in mammals. Heterologous cellular expression studies imply that TRPV4 confers responsiveness to hypotonicity (both aspects are reviewed by Liedtke & Kim, 2005).
Recent developments concerning function of TRPV4: regulation of TRPV4 channels by N-glycosylation, and critical roles of TRPV4 in cellular volume regulation and in lung injury
Another recent focus in the field of TRP ion channels is intracellular trafficking, post-translational modification and subsequent functional modulation. For TRPV4, it was reported in heterologous cells (HEK 293T) that N-glycosylation between transmembrane domain 5 and pore-loop (position 651) decreases osmotic activation via decreased plasma membrane insertion (Xu et al. 2006). Interestingly, N-glycosylation between transmembrane domains 1 and 2 had a similar effect on TRPV5, and the anti-ageing hormone KLOTHO could function in the same way as ß-glucuronidase and subsequently activate TRPV5 (Chang et al. 2005). Thus, it appears feasible that KLOTHO or related, KLOTHO-like hormones function as ß-glucuronidases to regulate insertion of TRPV4 into the plasma membrane. How critical this mechanism is in vivo remains to be determined.
TRPV4 also has been found to play a role in maintenance of cellular osmotic homeostasis. One particular cellular defense mechanism of tonicity homeostasis is regulatory volume change, namely regulatory volume decrease (RVD) in response to hypotonicity. In a recent paper, Bereiter-Hahn's group demonstrated that CHO immortalized tissue culture cells have a poor RVD which, after transfection with TRPV4, improved strikingly (Becker et al. 2005). In another study, Valverde's group showed that TRPV4 mediates the cell-swelling-induced Ca2+ influx into bronchial epithelial cells that triggers RVD via Ca2+-dependent potassium ion channels (Arniges et al. 2004). This cell swelling response did not function in cystic fibrosis (CFTR) bronchial epithelia, where, in contrast, TRPV4 could be activated by 4--PDD, leading to Ca2+ influx. This indicates that TRPV4 is downstream of the signalling step that is genetically defective in cystic fibrosis, the CFTR chloride conductance. These findings raise the intriguing possibility that activation of TRPV4 could be used therapeutically in cystic fibrosis. In another recent investigation, Ambudkar and colleagues found a concerted interaction of the water channel aquaporin 5 (AQP-5) with TRPV4 in hypotonic swelling-induced RVD of salivary gland epithelia (Liu et al. 2006). These findings shed light on molecular mechanisms operative in secretory organs that secrete watery fluids. This basic physiological mechanism appears to be maintained by a concerted interaction of TRPV4 and AQP-5, which was found to be dependent on the cytoskeleton. Taken together, TRPV4 also plays a role in regulatory volume decrease in response to tonicity-induced cell swelling, suggested for epithelial cells in airways and exocrine glands, but not in nerve cells. An exciting possibility is that TRPV4 could become a translational target in cystic fibrosis. Another aspect of lung function was elucidated recently (Alvarez et al. 2006). The alveolar septal barrier was injured in an ex vivo lung perfusion model by stimulating TRPV4 channels, found to be expressed in the alveolar septal wall, with 4--PDD and with 14,15-epoxyeicosatrienoic acid, another known activator of TRPV4. The permeability response to 4--PDD was absent in trpv4–/– mice, whereas the lung's response to thapsigargin, a toxin known to evoke release of Ca2+ from intracellular stores, remained independent of the genotype. In aggregate, these data strongly suggest that TRPV4 plays a critical role in the injury of the alveolar septal barrier. In view of this evidence, TRPV4 is a strong candidate to function as a molecular signalling mechanism critical for acute lung injury, e.g. lung oedema.
Mammalian TRPV4 directs osmotic avoidance behaviour in C. elegans: TRPV4 expression in ASH rescues osm-9 mechanical and osmotic deficits
In the genetic model organism C. elegans, TRPV4 was transgenically directed to ASH amphid neurones of osm-9 mutants. Surprisingly, TRPV4 expression in C. elegans ASH rescued osm-9 mutants' defects in avoidance of hypertonicity and nose touch (Liedtke et al. 2003). However, mammalian TRPV4 did not rescue the odourant avoidance defects of osm-9, suggesting that this function of TRPV channels differs between vertebrates and invertebrates. This basic finding of the rescue experiments in osm-9 ash::trpv4 worms has important implications for our understanding of mechanisms of signal transduction (see Fig. 2).
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While TRPV4 restores responsiveness to hypertonicity in C. elegans osm-9 mutants, it is only gated by hyposmotic stimuli in transfected mammalian cells. The reasons for this discrepancy are not understood, but it can be meaningfully speculated that the presence of ancillary transmembrane proteins that can function as push–pull converters is a critical factor. Not mutually exclusive is the hypothesis that the outer plasma membrane of the sensory cilium of the ASH sensory neurone is composed in a way that it leads to a phase reversal, response to hypotonicity versus response to hypertonicity. There is precedence of an involvement of the membrane concerning whether an ion channel (gramicidine, in this case) functions as stretch activated or as stretch inactivated.
Outlook for future research on TRPV channels
One topic for future investigation of TRP channels is the functional significance of protein–protein interactions of TRP(V) ion channels with to-be-discovered interaction partners (a particularly interesting example of protein–protein interactions of TRPV4 splice variants from airway epithelia was reported recently by Arniges et al. 2006; but see also Cuajungco et al. 2006). In addition, there is the obvious potential of TRP channels as targets for translational efforts (Nilius et al. 2005), such as secretory disorders (e.g. cystic fibrosis), pain and hydromineral homeostasis.
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Acknowledgements
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, USA), the Klingenstein Fund (New York, NY, USA) and by Duke University (Durham, NC, USA).
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