Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Transient Receptor Potential Cation Channel Subfamily V Member 4 (TRPV4)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101977


Historical Background

The transient receptor potential cation channel vanilloid isoform 4 (TRPV4), one of the six members of the TRPV subfamily, is a broadly expressed and versatile vertebrate cellular sensor. It was independently identified using candidate gene strategies as the vanilloid receptor-related osmotically activated channel (VR-OAC) in the central nervous system (CNS) (Liedtke et al. 2000) and the vanilloid receptor-like channel 2 (VRL-2) and osm-9-like TRP channel 4 (OTRPC4) in the kidney, liver, and heart (Strotmann et al. 2000). The gene encodes a nonselective cation channel with a slight preference for calcium (PCa/PNa = 6–10). The channel is a tetramer of four subunits that are polymodally activated by physical and chemical stimuli that include reduction in extracellular osmolarity, non-noxious temperature, acidity, eicosanoid metabolites, phorbol esters, and mechanical forces (cell swelling, pressure, stretch, and cytoskeletal “pull”). Expression studies show wide TRPV4 distribution across essential organs that include the heart, vasculature (arteries and capillaries), liver, placenta, lungs, bladder, testis, oviduct, kidneys, and the brain, where it is localized to neurons, glia, and blood vessels (Shibasaki 2016; White et al. 2016). Its closest vertebrate relative is the TRPV1 capsaicin receptor with 40.9% sequence identity, whereas the closest invertebrate homologues are inactive (iav), nanchung (nan), and osm-9, which regulate mechanotransduction and hearing in flies and worms, respectively.

Multimodal Gating and Modulation of TRPV4

Structure of TRPV4

The human TRPV4 channel is a ∼92 – 110 kDa protein consisting of 12 exons and 871 amino acids forming 5 possible splice variants (TRPV4A, TRPV4B, TRPV4C, TRPV4D, and TRPV4E) through excision of exons 2, 5, and/or 7; two splice products (TRPV4A and TRPV4D) can be inserted as functional channels in the plasma membrane. Translation of the full-length monomer (TRPV4A) results in six transmembrane (TM) α-helices with intracellular N- and C-termini, two cytosolic loops, and a cation-permeable pore located between S5 and S6 (Fig. 1). The four subunits composing the functional channel are assembled around the central aqueous pore with an outer gate and a selectivity filter (White et al. 2016) (Fig. 1). The N-terminal “finger” includes the scaffold consisting of six ankyrin repeat domains (ARDs) that are common to other members of the vanilloid subfamily. ARDs modulate protein-protein interactions (including subunit trafficking to the membrane and assembly into the functional tetramer) and protein-ligand interactions and contain binding sites for ATP, phosphoinositides (PI(4,5)P2), and calmodulin (CaM). A proline-rich domain, preceding the first ARD, binds PACSIN1-3 proteins, and was implicated in both mechanosensitivity and cytoskeletal remodeling. The C-terminus contains the conserved “TRP box” (the WKFQR consensus sequence), a CaM-binding domain that modulates channel tetramerization, gating, and desensitization, and a PDZ-binding-like domain that guides interaction with the many PDZ domain proteins (Fig. 1f). Crystallographic and NMR data on atomic structure of TRPV4 are not yet available; however, cryo-electron microscope data show an oblique orientation of the channel within the lipid bilayer (Shigematsu et al. 2010). Although homomerization is preferred, recent evidence uncovered heteromeric associations with TRPC1, TRPP2, and TRPV1 subunits.
Transient Receptor Potential Cation Channel Subfamily V Member 4 (TRPV4), Fig. 1

The TRPV4 gene and protein. The human gene maps on chromosome 12, at q24.1, encoding ( a , b ) 15 exons, ( c , d ) with 3229 bases and 839 amino acids. ( e ) Canonical TRPV structure based on six TM domains and the pore-forming S5-S6 loop. ( f ) Molecular features of the TRPV4 channel including the ARD domains in the N-terminus, and TRP, MAP7, and CaM domains in the C-terminus (Adapted from White et al. 2016 )

At least 38 proteins have been identified as binding partners of TRPV4 and implicated in the regulation of its trafficking, heteromerization, ubiquitination, and activation. The ER calcium sensor STIM1 may regulate TRPV4 trafficking, whereas phosphorylation by Src kinase, protein kinase A, protein kinase C, CaM kinase II, and glucocorticoid-induced protein kinase 1 (SGK1) modulates channel gating and hyperalgesia to mechanical/inflammatory stimuli (Fig. 2a). Association with caveolin-1 may be required for TRPV4 localization to cholesterol-rich lipid rafts. TRPV4 also interacts directly with multiple cytoskeletal components including F-actin, β-tubulin, integrins, AKAP-97, and neurofilaments and functionally interacts with ion channels localized within the same “microdomain.” These include large-conductance BK channels, KCa3.2, Kir4.1, TRPC1, and aquaporins (Ma et al. 2011; Iuso and Krizaj 2016).
Transient Receptor Potential Cation Channel Subfamily V Member 4 (TRPV4), Fig. 2

TRPV4 activation is sensitized by extrinsic and intrinsic stimuli and induces downstream remodeling of signaling pathways. ( a ) TRPV4 is activated by hypotonicity, synthetic agonists, and moderate heat, which may activate stretch-sensitive PLA 2 enzymes and regulate downstream Ca 2+ -dependent gene expression and cytoskeletal genes and proteins. PKA, SGK, PKC, and Src are protein kinases. ( b ) Swelling-induced TRPV4 activation is augmented by water influx through aquaporin channels (( a ) Modified from Darby et al. 2016 ; ( b ) Modified from Ryskamp et al. 2016 )

TRPV4 Currents and Pharmacology

TRPV4 gates nonselective cation fluxes with a moderate preference for Ca2+ over Na+, Ba2+, and Sr2+. The current-voltage relationship typically shows both outward and inward rectification but is linearized in retinal glia and transfected oocytes (Watanabe et al. 2002; Ryskamp et al. 2014; Toft-Bertelsen et al. 2017), possibly due to heteromerization with other TRPs. Depending on the cell type, the single-channel conductance generally varies between 50 and 70 pS.


The most commonly synthetic agonist for TRPV4 is GSK1016790A, a piperazine-linked compound with an EC50 in low nanomolar concentrations. The selectivity of another commonly used agonist, 4α-phorbol 12,13-didecanoate (4α -PDD), has been questioned (Alexander et al. 2013). TRPV4 is inhibited by the pan-TRP channel blocker Ruthenium Red and selective antagonists HC-067047, Rn1734, GSK205, and GSK2193874 with IC50s between nM (GSK2193874) and μM (HC-067047) concentrations (Vincent and Duncton 2011).


Similar to its TRPV1 cognate, TRPV4 is subject to facilitation/sensitization and inactivation/desensitization by diverse stimuli including intracellular Ca2+, which first potentiates then inactivates the channel via calmodulin. Sensitization (augmentation of the response to subsequent stimulation with the agonist) is induced by extracellular Ca2+, ATP, proinflammatory PAR-2 (protease-activated) receptors, and protein kinase A (Fig. 2). The channel is acutely desensitized by increases in [Ca2+]i, activation of CaM and also exhibits tachyphylaxis (reduction in the second response to the activating stimulus). CaM site interactions with the Ins(1,4,5)P3 receptor 3 (IP3R) may sensitize TRPV4 to EETs (epoxyeicosatrienoic acid metabolites of arachidonic acid) and mechanical stimuli. PIP2 binding to the N-terminus is required for activation by heat and hypotonic stimuli (Phelps et al. 2010; Garcia-Elias et al. 2013).

Activation by Swelling, Temperature, and Stretch

The ability to detect and respond to an increase in cell volume is critical for the survival of cells that lack cell walls (i.e., animal cells). TRPV4, originally identified as a swelling-activated channel (Strotmann et al. 2000), mediates hypotonicity-induced calcium increases following the phosphorylation of N-terminal tyrosine 110 (Vriens et al. 2004). In many cell types, TRPV4-induced [Ca2+]i elevations drive subsequent regulatory volume decrease (RVD), suggesting that TRPV4 contributes to the regulation of cell volume (Becker et al. 2005; Jo et al. 2015). While hypotonicity is a major physiological activator of TRPV4, it has been debated whether and to what extent swelling-induced TRPV4 is gated by mechanical forces associated with swelling-induced stretch of the lipid bilayer, enzymatic cascades associated with phospholipase A2 (PLA2), and the submembrane cytoskeleton. Although PLA2 and cytochrome P450 inhibitors typically suppress swelling-induced TRPV4 activation (Watanabe et al. 2003), hypotonicity activates TRPV4 in (i) yeast, which lacks endogenous PLA2, (ii) membrane patches excised from frog oocytes with absent intracellular modulators, and (iii) neurons in which TRPV4 is resistant to PLA2 blockers (and likely activated by mechanical tension within the lipid bilayer; Lechner et al. 2011; Ryskamp et al. 2014; Rocio Servin-Ventes et al. 2017). Further indicative of mechanosensory function are the observations that exogenous and endogenous pressure, shear flow, membrane stretch, cell suction, and pulling on β1 integrins or deflections of the extracellular substrate activate TRPV4 (Loukin et al. 2010; Matthews et al. 2010; Ryskamp et al. 2016 Rocio Servin-Ventes et al. 2017). In astroglial and epithelial cells, TRPV4 activation is noticeably augmented by aquaporins (AQP1, AQP4, AQP5), which regulate the rate of swelling-induced membrane stretch (Jo et al. 2015, 2016; Mola et al. 2016).

With a Q10 of ∼20, TRPV4 has been implicated in thermosensation and possibly thermoregulation. In the majority of species, TRPV4 is activated when ambient temperature is increased above ∼25 °C and inactivated when it exceeds ∼40 °C. Hence, the channel that may not respond to mechanical stress at room temperature shows maximal activation by hypotonicity, substrate stretch, and phorbol esters around the core body temperature (∼34–37 °C) (Güler et al. 2002). Thermosensitivity may be absent in nonmammalian cells and lost when recorded with inside-out patches of overexpressing HEK293 cells or following the deletion of ARDs. Intriguingly, the peak sensitivity of the hypotonicity-induced TRPV4 response in avians (which have higher core temperatures than mammals) is >40 °C. Another remarkable finding was that temperature activation of TRPV4 contributes to sex determination in the American alligator (Alligator mississippiensis), an apex predator endemic to the southeastern United States. Eggs incubated at 33 °C yield male offspring, whereas incubation temperatures below 30 °C increase the likelihood of hatching female offspring (Watanabe et al. 2002; Yatsu et al. 2015).

TRPV4 Activation by Endogenous Ligands

The TRPV4 activation mechanism in native cells has not been fully elucidated but may involve at least three not mutually independent mechanisms. In the majority of cells, as well as in recombinant cells that overexpress the channel, TRPV4 activation by swelling and synthetic agonists typically involves intermediary steps downstream of phospholipase A2 (PLA2), which catalyzes hydrolysis of arachidonic acid. The EET metabolites such as 5,6-EET, 8,9-EET, and 11,12-EET, which were shown to open TRPV4 in vascular endothelia, ocular epithelia, and astroglial cells (Jo et al. 2016) and are believed to function as the final common activators of the channel (Fig. 2b) (Watanabe et al. 2003). TRPV4 may also be sensitive to endocannabinoids (amides and esters of long-chain polyunsaturated fatty acids) such as anandamide (AEA) and 2-arachydonyl glycerol (2-AG) (Watanabe et al. 2003). Second, Src kinase-mediated phosphorylation was proposed to be necessary for TRPV4 activation in the kidney and lens (Shahidullah et al. 2015). Third, in neurons (visceral neurons and retinal ganglion cells) and chondrocytes, mechanoelectrical transduction mediated by TRPV4 appears to be rapid and independent of PLA2 (Lechner et al. 2011; Ryskamp et al. 2014; Rocio Servin-Ventes et al. 2017).

Localization and Physiological Function of TRPV4

TRPV4 channels play important functions in the CNS and key organs and tissues (heart, lung, bone, cartilage, kidney, bladder, oviduct, retina) as cellular sensors of local and systemic osmolarity, temperature, lipid metabolites, and mechanical stress. Widely expressed across vertebrate phyla they are particularly strongly expressed across sensory organs, imbuing nociceptive, auditory, ocular, vestibular, proprioceptive pathways with the sensitivity to temperature, activity-dependent osmotic gradients, and mechanical forces. Importantly, TRPV4 regulates barrier function in many (probably most) epithelia and endothelia. Knockout mice are fertile but show a variety of phenotypes including increased blood osmolality, reduced water intake and vasopressin synthesis, larger bladder capacity, compromised vascular function, elevated acoustic thresholds, and deficient transduction of mechanical, thermal, and nociceptive stimuli. Its invertebrate homologues (iav and Nan) are essential for hearing. Detailed elaboration of tissue- and cell type-specific functions of TRPV4 channels is beyond the scope of this report; however, the reader is referred to excellent recent reviews (Darby et al. 2016; Tomilin et al. 2016; White et al. 2016).


TRPV4 has an indisputable function in local and systemic CNS/PNS tonicity-sensing and volume regulation. It is expressed in subsets of neurons, astroglia, microglia, ependymal cells of the choroid plexus, vascular endothelia and was implicated vasculo-neuronal, gliovascular, and neurovascular coupling. The highest expression level of TRPV4 was detected in the choroid plexus in which the channel was proposed to modulate water transport and cell volume regulation through anoctamin 1 (ANO1), a Ca2+-activated chloride channel (Takayama et al. 2014). Neurons express the channel in dendrites/synapses, somata, and axons (Ryskamp et al. 2011; Shibasaki et al. 2015), whereas the astroglial channel is predominantly localized to the end-foot compartment where it colocalizes with the aquaporin 4 water channel (Jo et al. 2015). By sensing the speed of cell swelling, TRPV4 activation believed to regulate water transport between the vasculature and brain, and may turn out as a major player in mediating the pathological, calcium-dependent, consequences of brain brain swelling, traumatic injury, and epilepsy (Iuso and Krizaj 2016; Toft-Bertelsen et al. 2017). Whether TRPV4 is expressed in microglia and its role in innate immune signaling is unclear.


TRPV4 plays a role in sensory and central processing in the vertebrate brain. Studies in cortical, hippocampal, and substantia nigra neurons, retinal ganglion cells (RGCs), hair cells, and vestibular ganglion neurons revealed its function as a transducer of osmolality and temperature shifts into neuronal [Ca2+]i. Constitutive activation of the channel by core body temperatures may depolarize hippocampal neurons and modulate pre- and/or postsynaptic signals such as neurotransmitter release and glutamate receptor activation (Shibasaki et al. 2007; Sudbury and Bourque 2013). In addition to local sensing of hypotonicity and mechanical forces, TRPV4 also functions as a systemic osmosensor. Cells in the paraventricular nucleus of the anterior hypothalamus employ TRPV4 channels to sense and regulate changes in blood osmolality, blood pressure, and heart rate. Accordingly, TRPV4 knockout mice consume less water, have higher serum osmolality, and produce less antidiuretic hormone (ADH) than their wild-type counterparts (Liedtke and Friedman 2003). Likewise, the supraoptic nucleus of the hypothalamus may utilize TRPV4 as a regulator of central thermosensing to defend the body against heat-induced dehydration (Sudbury and Bourque 2013). Furthermore, it was proposed that TRPV4 regulates body temperature in the preoptic area of the hypothalamus (Guler et al. 2002). In cerebral ischemic injury, TRPV4 activation leads to the phosphorylation of p38 MAPK, reduction of bcl-2/Bax protein ratio, increase in cleaved caspase-3, and apoptosis in retinal and cortical neurons (Ryskamp et al. 2011; Jie et al. 2015). Thus, depending on conditions within the brain, TRPV4 may serve as as a pro- or anti-apoptotic mechanism.


TRPV4 is a key player in somatosensory and visceral pain and also acts as a detector of physiological changes in blood osmolality produced by physiological water intake. The channel is expressed in epidermal Merkel cells, subsets of dorsal and ventral spinal root neurons, thoracic sensory afferents, trigeminal afferents innervating the dura mater, sympathetic and parasympathetic fibers that innervate the intestine, sweat glands, kidneys and liver, myenteric neurons, and satellite glial cells. It regulates mechanical and thermal hyperalgesia in primary afferent nociceptive fibers. Perception of pain is correlated with phosphorylation of TRPV4 by PKA and PKC, activation of PAR-2, and/or stimulation of the MEK/ERK pathway. Intriguingly, activation of keratinocyte TRPV4 by UVB may trigger sunburn pain through purinergic, NGF-mediated signaling to somatosensory afferent nerve endings (Moore et al. 2013). Similarly, TRPV4 may contribute to sensation of chronic itch that plagues ∼10% of the population. The mechanism underlying this condition involves serotonergic DRG neurons which express TRPV4 instead of TRPV1 channels, which are localized to histaminergic neurons that regulate most forms of itch sensing (Akiyama et al. 2016).

Cardiovascular System

TRPV4 is ubiquitous across vascular endothelia, smooth muscle cells, perivascular sensory nerves, and astrocytic end feet in many, possibly most, vascular beds (pulmonary, aortic, cerebral, and retinal) in which it regulates both vascular diameter and tone. It can be activated by shear flow and intraluminal pressure, leading to local Ca2+ increases (“sparklets”) that stimulate Ca2+-dependent IP3 receptors and K+ (KCa3.3 and KCa3.1) channels which hyperpolarize and dilate the endothelium. Its activation requires arachidonic acid, PLA2, and production of various EETs (Watanabe et al. 2002; Willette et al. 2008; Baylie and Brayden 2011; Filosa et al. 2013). In smooth muscle cells, TRPV4 subunits were proposed to heteromerize with TRPC1 channels and regulate contractility via functional coupling to ryanodine receptors and KCa1.1 channels, possibly within lipid raft domains (Ma et al. 2011; Guéguinou et al. 2014). In addition to directly responding to shear flow, vascular TRPV4 channels contribute to vasodilation mediated by nitric oxide, prostacyclin PGI2, and acetylcholine, while driving the endothelium-derived hyperpolarizing factor (EDHF) mechanisms that control the resistance of arteries and arterioles and regulate the myogenic tone.

TRPV4 channels additionally regulate blood pressure through their effects on the sympathetic system. Systemic administration of GSK1016790A caused a hyper-relaxation of blood vessels; a corresponding drop in blood pressure; severe vascular leakage in the lung, intestine, and kidney; and ultimately a total circulatory collapse (Everaerts et al. 2010). TRPV4-mediated vasodilation is absent in TRPV4−/− mice (Mendoza et al. 2010).


TRPV4 is prominently expressed in the lung (alveolar macrophages, vascular endothelial cells, and alveolar epithelial cells), kidney (nephronal epithelia), urinary bladder, bone (osteoblasts, osteoclasts), cartilage (chondrocytes), the GI tract (brush-border epithelial cells), and water-impermeant segments of the kidney, as well as the visceral and bronchopulmonary nociceptor afferents that innervate these tissues. In the lung, TRPV4 maintains the structural integrity of the alveolar unit by coupling fluid viscosity to the beat frequency of airway epithelial cilia and by regulating the cell volume, endothelial barrier permeability, and integrity. Excessive stimulation may induce airway constriction and contribute to acute lung injury, edema, and cystic fibrosis, whereas alveolar leakiness is absent in TRPV4−/− mice (Jian et al. 2008; Lorenzo et al. 2008). The channel is also expressed in bladder urothelium and smooth muscle cells, where it may function as a mechanosensor monitoring bladder distension and voiding. Consequently, pharmacological stimulation of TRPV4 overactivates the bladder, whereas TRPV4-KO mice have an increased voiding threshold (Thorneloe et al. 2008), attenuated Ca2+ increase in response to membrane stretch together with reduced stretch-induced ATP release (Mochizuki et al. 2009). Gastric epithelial cells likewise show TRPV4-dependent ATP release which may be compromised following the infection with Helicobacter pylori (Mihara et al. 2016).

TRPV4 Channelopathies

Gain- and loss-of-function mutations in TRPV4 are associated with a wide spectrum of inherited human diseases. Depending on the mutated residue, the phenotypes include disabling and even lethal autosomal skeletal abnormalities (dysplasias) and sensorimotor neuropathies that involve topographically distinct muscles and nerves. While the structure-function relationships have not been determined for most of TRPV4 mutation-causing diseases, disease severity correlates with the extent of change in TRPV4 activation (either gain- or loss-of-function) and suppression by PI(4,5)P2 (Loukin et al. 2010; Takahashi et al. 2014). There are no animal models of human TRPV4 channelopathies. In contrast to the debilitating consequences of TRPV4 mutations in humans, the TRPV4 knockout phenotype in mice is relatively mild (Liedtke and Friedman 2003; Suzuki et al. 2003).

Skeletal Dysplasias

Over 70 recognized single amino acid substitutions across the entire human TRPV4 gene cause musculoskeletal diseases characterized by short stature, platyspondyly (flattening of vertebrae), and defects in bone ossification (arthropathy). The diseases include spondyloepiphyseal dysplasia (SED), dominant brachyolmia type 3 (BO3), and metatropic dysplasias that do not involve ocular changes (Nilius and Voets 2013; McNulty et al. 2015). The symptoms range from mild scoliosis, shortening of torso, limbs, and digits to embryonic lethality. Excessive Ca2+ influx from gain-of-function mutations in the ARD domain was proposed to inhibit bone formation via the regulation of BMP (Leddy et al. 2014). A distinct syndrome is familial digital arthropathy-brachydactyly (FDAB), a form of dwarfism characterized by irregular development of joints of finger and toes and a painful osteoarthritis. Loss-of-function mutations are more closely associated with erosion of cartilage tissue and enlargement of the ends of the long bones.

TRPV4 Neuropathies

TRPV4 mutations are a major cause of hereditary neuropathies, resulting in motor or sensory deficits caused by axonal degeneration. The syndromes include One prominent example is the Charcot-Marie-Tooth disease type 2C (CMTC2), the most common inherited neuromuscular disorder afflicting 1 in 2500 people associated with sensorineural hearing loss, bladder urgency, compromised respiration, and diaphragm and laryngeal muscle rigidity (Landouré et al. 2009). Fifty-nine percent of individuals with CMTC2 also have bilateral hearing loss. CMTC2 results from ARD mutations leading to constitutive and excitotoxic activation of TRPV4. Transfection of CMT2C mutations into dorsal root ganglia (DRGs) neurons and HEK293 cells markedly increased [Ca2+]i and resulted in four-fold increase in cell death (Landouré et al. 2009). Other syndromes include the congenital distal spinal muscle atrophy (CDSMA) and scapuloperoneal spinal muscular atrophy (SPSMA). Roughly 10% of SMAs can be attributed to loss-of-function mutations in TRPV4; however, in contrast to CMTC2, patients diagnosed with SMAs lack sensory deficits. TRPV4 overactivation increases the excitability of retinal ganglion cells (RGCs) leading to calcium overload and apoptosis implicated in abnormal pressure sensing and optic neuropathy (Ryskamp et al. 2011). Neuropathies may be caused by impaired TRPV4 role in neuritogenesis.

3.2 Chronic Obstructive Pulmonary Disease (COPD), Pulmonary Hypertension, and Acute Respiratory Distress Syndrome

COPD is a chronic emphysema disease associated with damage of lung airway epithelia, bronchoconstriction, parenchymal destruction, and hypersecretion of mucus. There is an association between TRPV4 polymorphisms and COPD (Kaneko and Szallasi 2014).


Widely distributed across mammalian organ systems and with homologous channels in invertebrates (White et al. 2016), TRPV4 represents a highly flexible and adaptable protein channel that is essential for diverse cellular processes. The activity of TRPV4 critically depends on tissue, cell type, and stimulus context. The severe skeletomuscular dysplasias and neuropathies resulting from genetic mutations in TRPV4 highlight the importance of the channel in maintaining homeostasis in cartilage, bone, and neural tissue (Nilius and Voets 2013) as well as in endothelial and epithelial tissues across the vertebrate body. Investigations into single modality activation of TRPV4 are often made difficult by interactions or presence of multiple activators warranting careful scrutiny of experimental conditions. Integration of TRPV4 into many different multi-protein complexes in conjunction with multimodal gating allows for the high degree of adaptability required for different functions.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Sarah N. Redmon
    • 1
  • Koji Shibasaki
    • 2
  • David Križaj
    • 1
  1. 1.Department of Ophthalmology and Visual SciencesJohn A. Moran Eye CenterSalt Lake CityUSA
  2. 2.Department of Molecular and Cellular NeurobiologyGunma University Graduate School of MedicineMaebashiJapan