Review
The vanilloid transient receptor potential channel TRPV4: From structure to disease

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Abstract

The Transient Receptor Potential Vanilloid 4 channel, TRPV4, is a Ca2+ and Mg2+ permeable non-selective cation channel involved in many different cellular functions. It is activated by a variety of physical and chemical stimuli, including heat, mechano-stimuli, endogenous substances such as arachidonic acid and its cytochrome P450-derived metabolites (epoxyeicosatrienoic acids), endocannabinoids (anandamide and 2-arachidonoylglycerol), as well as synthetic α-phorbol derivatives. Recently, TRPV4 has been characterized as an important player modulating osteoclast differentiation in bone remodelling and as a urothelial mechanosensor that controls normal voiding. Several TRPV4 gain-of-function mutations are shown to cause autosomal-dominant bone dysplasias such as brachyolmia and Koszlowski disease. In this review we comprehensively describe the structural, biophysical and (patho)physiological properties of the TRPV4 channel and we summarize the current knowledge about the role of TRPV4 in the pathogenesis of several diseases.

Introduction

The superfamily of Transient Receptor Potential (TRP) cation channels comprises unique sensory proteins that are expressed in almost every tissue and cell type, and play an important role in diverse homeostatic functions. They are divided into seven subfamilies: the TRPC (‘Canonical’), TRPV (‘Vanilloid’), TRPM (‘Melastatin’), TRPP (‘Polycystin’), TRPML (‘Mucolipin’), the TRPA (‘Ankyrin’), and TRPN (‘NOMP-C’) (Clapham, 2003, Damann et al., 2008, Inoue et al., 2006, Liedtke and Kim, 2005, Montell, 2003, Montell, 2005, Nilius, 2007, Owsianik et al., 2006a, Owsianik et al., 2006b, Pedersen et al., 2005, Ramsey et al., 2006, Voets et al., 2005). Only few channelopathies in which mutations of TRP genes are the direct cause of cellular dysfunction have been identified so far (Nilius et al., 2007). However, in many cases mapping of TRP genes to susceptible chromosome regions or correlations between levels of the channel expression and disease symptoms strongly indicate the involvement of these channels in pathophysiological processes that lead to different disease states. Importantly, TRP channels are direct targets for irritants, inflammation mediators and xenobiotic toxins and, therefore, are also involved in some systemic diseases. In this review we focus on the TRPV subfamily member, TRPV4, and its role in pathogenesis of various diseases.

Section snippets

Structural insights

On the basis of structure and function, the TRPV family comprises four groups : TRPV1/TRPV2, TRPV3, TRPV4 and TRPV5/6 (see for a review Benham et al., 2002, Gunthorpe et al., 2002, Vennekens et al., 2008). TRPV1-4 are thermosensitive, polymodal, non-selective cation channels (Benham et al., 2002, Nilius et al., 2004, Nilius et al., 2003) that are modestly permeable to Ca2+, with a permeability ratio PCa/PNa between ∼1 and 10 (Alexander et al., 2004, Clapham, 2003, Nilius et al., 2004). TRPV5

Trafficking

The sorting of TRPV4 from the ER seems to depend on the C-terminal residues that might be involved in oligomerization of the channel. A complete deletion of the C terminus of TRPV4 prevents translocation of the channel to the plasma membrane. Truncations of the last 27 or 43 C-terminal amino acids (Δ844 or Δ828) result in partial retention in the ER, whereas all deletions upstream of amino acid 828 resulted in the complete ER retention (Becker et al., 2008).

The insertion of TRPV4 into the

TRPV4 expression

In the urinary system, TRPV4 is expressed in epithelial cells lining the constitutively or conditionally (antidiuretic hormone (ADH)-dependent) water impermeable segments of the nephron (Tian et al., 2004). More caudally TRPV4 is abundantly expressed in the urothelial cells lining the renal pelvis, ureters, urinary bladder and urethra (Birder et al., 2007, Gevaert et al., 2007b).

In the respiratory system, TRPV4 is highly expressed in airway epithelia of the trachea and the lungs. It is

Biophysical properties of TRPV4

Currents through TRPV4 reverse near 0 mV and are clearly carried by cations. With Ca2+ or Mg2+ as the only permeating extracellular cation, an inward current can be measured indicating that both divalent cations can permeate TRPV4 channels with permeabilities relative to Na+ of 6–10 for Ca2+ and 2–3 for Mg2+ (Voets et al., 2002, Watanabe et al., 2002a, Watanabe et al., 2002b, Watanabe et al., 2003a). Typical current–voltage relationship (IV) curves are slightly inwardly and outwardly

Osmo- and mechanostimulation

TRPV4 can be activated in the cellular response to hypotonicity, and therefore, it has been considered as a mechano- or osmosensor (Liedtke, 2005, Liedtke et al., 2000, Nilius et al., 2001a, Nilius et al., 2004, Strotmann et al., 2000). Nevertheless, effects of mechano-stimuli on TRPV4 seem to be indirect since activation by cell-swelling or shear stress is relatively slow. It is very likely that mechano-stimuli are sensed by phospholipase A2 (PLA2), leading to production of arachidonic acid

PACSIN3

TRPV4 functionally interacts with PACSIN3, a protein that is implicated in vesicle trafficking by blocking dynamin-mediated endocytosis (Cuajungco et al., 2006). The PACSIN3 interaction site is localized in the N-terminal proline-rich domain of TRPV4. This proline-rich domain of TRPV4 does not have a counterpart in other members of the TRPV subfamily, explaining why PACSIN3 selectively binds to TRPV4 and not to other TRPV channels (D'hoedt et al., 2007). Co-expression of PACSIN 3, but not of

Physiological functions of TRPV4

Widespread expression of TRPV4 throughout the different organs suggests its involvement in many physiological processes. The first idea about physiological process that might implicate TRPV1-4 came from invertebrates. Osm-9, one of the five Caenorhabditis elegans TRPV channels, is expressed in chemo-sensory, mechano-sensory and osmo-sensory neurons. The loss of OSM-9 in transgenic worms results in defective olfactory, mechano-sensory and osmo-sensory responses (Colbert et al., 1997). Moreover,

TRPV4-related channelopathies

Mutations in TRPV4 produce a broad spectrum of autosomal dominant skeletal dysplasias, ranging from mild brachyolmia over spondylomethaphyseal dysplasia (SMD) to severe metatropic dysplasia (Rock et al., 2008, Krakow et al., 2009).

The autosomal dominant brachyolmia is a rather mild type of bone dysplasia characterized by short stature, short trunk, scoliosis and typical radiologic features such as platyspondyly with overfaced vertebral pedicels (Fig. 5B). Two point mutations in TRPV4

Concluding remarks

With a wide-spread expression pattern and various activation mechanisms, TRPV4 is a flexible channel that regulates diverse cellular functions in the sense of a fine-tuning rather than an “all-or-nothing” behaviour. Such physiological characteristic also explains multiple phenotypes of TRPV4 knockout models that are not lethal but lack correct regulation of different cellular processes.

Although TRPV4 is one of the most studied channels of the entire TRP superfamily, a lot of important issues

Note added in proof

Very recently published studies demonstrate that mutations in TRPV4 result in scapuloperoneal spinal muscular atrophy and Charcot-Marie-Tooth disease type 2C, two common inherited neurodegenerative diseases characterized by sensory defects and muscle weakness (Auer-Grumbach et al., 2010, Deng et al., 2010, Landouré et al., 2010, Nilius and Owsianik, 2010).

Acknowldegements

We thank all members of the Laboratory of Ion Channel Research Leuven for helpful discussions. This work was supported by grants from the Belgian Federal Government (IUAP P5/05), the Research Foundation-Flanders (G.0172.03, G.0149.03, G.0565.07 and G.0686.09), the Astellas European Foundation award 2009 and the Research Council of the KU Leuven (GOA 2004/07 and EF/95/010), Wouter Everaerts is a doctoral fellow of the Research Foundation-Flanders.

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