Transient receptor potential cation channel subfamily V member 4

Definition:

Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by heat, low pH, citrate and phorbol esters. Increase of intracellular Ca(2+) potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism. Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers (By similarity). Acts as a regulator of intracellular Ca(2+) in synoviocytes. Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8. Together with PKD2, forms mechano- and thermosensitive channels in cilium. Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes (By similarity). Regulates expression of chemokines and cytokines related to pro-inflammatory pathway in adipocytes (By similarity). Together with AQP5, controls regulatory volume decrease in salivary epithelial cells (By similarity). Required for normal development and maintenance of bone and cartilage. In its inactive state, may sequester DDX3X at the plasma membrane. When activated, the interaction between both proteins is affected and DDX3X relocalizes to the nucleus.; [Isoform 5]: Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by phorbol esters. Has the same channel activity as isoform 1, and is activated by the same stimuli.; [Isoform 2]: Lacks channel activity, due to impaired oligomerization and intracellular retention.; [Isoform 4]: Lacks channel activity, due to impaired oligomerization and intracellular retention.; [Isoform 6]: Lacks channel activity, due to impaired oligomerization and intracellular retention.; (Microbial infection) Facilitates hepatitis C virus (HCV) replication, possibly through its action on DDX3X.; (Microbial infection) Facilitates Dengue virus (DENV) replication, possibly through its action on DDX3X.; (Microbial infection) Facilitates Zika virus (ZIKV) replication, possibly through its action on DDX3X.

References:

[1]. Guida Landouré, et al. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet. 2010 Feb;42(2):170-4. [Content Brief]

[2]. Michael Köttgen, et al. TRPP2 and TRPV4 form a polymodal sensory channel complex. J Cell Biol. 2008 Aug 11;182(3):437-47. [Content Brief]

[3]. Matthew J Rock, et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet. 2008 Aug;40(8):999-1003. [Content Brief]

[4]. Shireen R Lamandé, et al. Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nat Genet. 2011 Oct 2;43(11):1142-6. [Content Brief]

[5]. P Doñate-Macián, et al. The TRPV4 channel links calcium influx to DDX3X activity and viral infectivity. Nat Commun. 2018 Jun 13;9(1):2307. [Content Brief]

[6]. R Strotmann, et al. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol. 2000 Oct;2(10):695-702. [Content Brief]

[7]. Nobuaki Takahashi, et al. TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P₂. Nat Commun. 2014 Sep 26;5:4994. [Content Brief]

[8]. Lauren Hurd, et al. A mutation in TRPV4 results in altered chondrocyte calcium signaling in severe metatropic dysplasia. Am J Med Genet A. 2015 Oct;167A(10):2286-93. [Content Brief]

[9]. Yuka Itoh, et al. An environmental sensor, TRPV4 is a novel regulator of intracellular Ca2+ in human synoviocytes. Am J Physiol Cell Physiol. 2009 Nov;297(5):C1082-90. [Content Brief]

[10]. Anna Garcia-Elias, et al. IP3 receptor binds to and sensitizes TRPV4 channel to osmotic stimuli via a calmodulin-binding site. J Biol Chem. 2008 Nov 14;283(46):31284-8. [Content Brief]

[11]. Maite Arniges, et al. Human TRPV4 channel splice variants revealed a key role of ankyrin domains in multimerization and trafficking. J Biol Chem. 2006 Jan 20;281(3):1580-6. [Content Brief]

[12]. Rainer Strotmann, et al. Ca2+-dependent potentiation of the nonselective cation channel TRPV4 is mediated by a C-terminal calmodulin binding site. J Biol Chem. 2003 Jul 18;278(29):26541-9. [Content Brief]

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