Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101909

Synonyms

Historical Background

Transient receptor potential vanilloid type 2 (TRPV2) was identified independently by two groups in 1999. Vanilloid receptor-like protein 1 (VRL-1) was identified as a cation channel structurally related to TRPV1, the capsaicin receptor (Caterina et al. 1999). TRPV2 was also identified as a calcium-permeable channel regulated by growth factors such as insulin-like growth factor-I and epidermal growth factor (Kanzaki et al. 1999). Human cDNA for TRPV2 encodes 764 amino acids, and mouse cDNA for TRPV2 encodes 756 amino acids. At the protein level, human and mouse TRPV2 share approximately 50% sequence identity with TRPV1. TRPV2 has six transmembrane segments, and the N-terminus of TRPV2 contains six ankyrin repeats. The channel molecule which is related to TRPV2 is expressed in various species. In C. elegans, OSM-9, a homologue of TRPV2, is expressed and involved in mechanosensation and olfaction (Colbert et al. 1997). In Drosophila melanogaster, Nanchung and Inactive, two members of the TRPV family, are involved in hearing sensation (Kim et al. 2003).

Regulation of TRPV2

TRPV2 is a calcium-permeable cation channel expressed ubiquitously in the body. It has six transmembrane domains (S1–S6), and a pore-forming loop is located between S5 and S6. In the C-terminal cytoplasmic domain, the TRP domain and binding sites for phosphatidylinositol 4,5-bisphosphate and calmodulin have been found (Mercado et al. 2010; Holakovska et al. 2011). The TRP domain is thought to be critical for homotetramerization. When expressed in a Xenopus oocyte, TRPV2 mediates cationic current with a permeability sequence of Ca2+ > Mg2+ > Na+ 〜 Cs+ > K+. When TRPV2 is expressed in HEK293 cells, the TRPV2 current is increased at a temperature above 52 °C. Accordingly, TRPV2 is thought to be a member of the thermo-TRP family (Caterina et al. 1999; Tominaga and Caterina 2004). The physiological significance of the heat-induced activation is, however, not certain at present. Another interesting regulation of TRPV2 is receptor-mediated translocation of the channel molecule. In an unstimulated condition, the majority of TRPV2 is located in the intracellular pool, mainly in the endoplasmic reticulum (ER). When stimulated by ligands including growth factors and cytokines, TRPV2 translocates from ER to the plasma membrane and functions as a Ca2+-permeable channel (Fig. 1) (Kanzaki et al. 1999; Boels et al. 2001, Hisanaga et al. 2009). This translocation of TRPV2 is mediated by the receptor-mediated activation of phosphatidylinositol 3-kinase (PI 3-kinase) and small GTPase Rac (Kanzaki et al. 1999; Nagasawa and Kojima 2012). Upon removal of the ligands, TRPV2 is internalized by endocytosis by a mechanism involving a GTPase dynamin (Nagasawa and Kojima 2012). Collectively, TRPV2 is the channel, intracellular localization which is regulated by various ligands. Regarding the expression in the plasma membrane, TRPV2 is not distributed diffusely in the cell surface. Rather, it is accumulated in the focal adhesion and, in some types of cells, in podosomes (Nagasawa and Kojima 2012). In macrophages, for example, TRPV2 is localized mainly in endoplasmic reticulum in unstimulated conditions. When stimulated by a chemotactic peptide fMetLeuPhe, TRPV2 translocates to the plasma membrane and is accumulated in the podosome, a special machinery regulating adhesion and migration of macrophages (Nagasawa et al. 2007; Nagasawa and Kojima 2012). An interesting feature of TRPV2 is that it also functions as a mechanosensitive channel. In cells expressing TRPV2, administration of a mechanical stimulus induces calcium influx, which is inhibited by blocking TRPV2 (Nagasawa and Kojima 2015). Two mechanisms are involved in stimulation of calcium influx induced by mechanical stress. First, mechanical stress induces translocation of TRPV2 to the site receiving the mechanical force. Second, mechanical stress activates TRPV2 by facilitating the gating of the channel (Nagasawa and Kojima 2015). As a mechanosensitive channel, TRPV2 is involved in the osmosensing in vasopressin-secreting neurons, detection of shear stress in endothelial cells, and sensing of osmotic changes in the oral mucosa and urothelium.
Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2), Fig. 1

Translocation of TRPV2. Majority of TRPV2 is located in ER in unstimulated condition. When stimulated by ligands, TRPV2 translocates to the plasma membrane by a mechanism involving PI 3-kinase and subsequent activation of Rac. TRPV2 functions as a calcium-permeable channel in the plasma membrane. When the ligand stimulation is terminated, TRPV2 is internalized gradually by dynamin-dependent endocytosis

Regulation of Cellular Functions by TRPV2

TRPV2 is expressed ubiquitously in the body. In certain tissues and organs, the expression of TRPV2 is significantly high. For example, TRPV2 is abundantly expressed in the central nervous system, particularly in neurons. In addition, various types of neuroendocrine cells, including enteroendocrine cells and pancreatic β-cells, express a high amount of TRPV2. In the cardiovascular system, TRPV2 is expressed in vascular smooth muscle cells and in endothelial cells. These cells sense mechanical and shear stresses. In the immune system, TRPV2 is abundantly expressed in macrophages and lymphocytes. TRPV2 is significantly expressed in the oral mucosa and larynx (Shimohira et al. 2009; Hamamoto et al. 2008), tissues exposed to hypotonicity and mechanical stresses. Also, significant expression of TRPV2 is found in the bladder epithelium, which senses changes in osmolarity and mechanical stresses.

TRPV2 is expressed abundantly in the brain and spinal cord during development (Cahoy et al. 2008). TRPV2 is important for development of neurons since it is critical for neurite outgrowth. In growing neurons, TRPV is localized in the growth cone and is activated by receiving mechanical stresses (Shibasaki et al. 2010). In neurons of the dorsal root ganglion, significant expression of TRPV2 is observed. TRPV2 may be involved in nociception. It is also possible that TRPV2 and TRPV1 form a heterodimer and modulate nociception in the hypothalamus. TRPV2 is expressed in neurons in the supraoptic and paraventricular nuclei. These neurons sense changes in the plasma osmolarity and secrete vasopressin. TRPV2 functions as a mechanosensitive channel, senses membrane stretch, and thereby regulates secretion of vasopressin.

In pancreatic β-cells, TRPV2 is regulated by insulin released from the cells. Insulin secreted from β-cells acts on the insulin receptor on the same cells, activates PI 3-kinase, and induces translocation of TRPV2 to the plasma membrane leading to an augmentation of Ca2+ entry. Thus, insulin acts as an autocrine factor and further stimulates its secretion by increasing Ca2+ entry (Hisanaga et al. 2009).

TRPV2 also plays important roles in the cardiovascular system. In vascular smooth muscle cells, TRPV2 functions as a mechanosensitive channel and is modulated by membrane stretch (Muraki et al. 2003). Together with TRPV4, TRPV2 is involved in the regulation of the vascular tone. Vascular endothelial cells also express TRPV2. These cells face the bloodstream, which causes shear stress in the cell surface. TRPV2 is a major molecule-sensing shear stress in endothelial cells. Significant expression of TRPV2 is also found in cardiomyocytes. With regard to the function of TRPV2 in cardiomyocytes, cardiac contractility is markedly increased by pharmacological activation of TRPV2 in vivo, which is not observed in TRPV2-null heat (Koch et al. 2012). TRPV2 is involved in pathophysiology of cardiomyocytes. Thus, cell-surface expression of TRPV2 is increased in cardiomyocytes derived from muscular dystrophic animals, which presumably causes Ca2+ overload. Reduction of the cell-surface expression of TRPV2 improves pathological changes in the dystrophic heart (Iwata et al. 2009).

In the immune system, TRPV2 is involved in both innate and adaptive immune responses (Santoni et al. 2013). In macrophages, expression of TRPV2 is high, and, in fact, TRPV2 is the only TPRV channel expressed in these cells (Yamashiro et al. 2010). A chemotactic peptide fMetLeuPhe activates PI 3-kinase and induces translocation of TRPV2 to the plasma membrane (Nagasawa et al. 2007). Inhibition of TRPV2 attenuates calcium entry induced by fMetLuePhe and blocks fMetLeuPhe-induced migration. In addition to the regulation of migration, activation of TRPV2 is indispensable for phagocytosis of macrophages. Granulocytes also express TRPV2, which is required for migration and phagocytosis. In addition, TRPV2 is involved in adaptive immune response. Thus, both CD4+ and CD8+ T cells express TRPV2. When T cells make contact with antigen-presenting cells, TRPV2 forms a complex with Kv1.3, KCa3.1, STIM1, and Orai (Lioudyno et al. 2008). Without TRPV2, Ca2+ response to antigen presentation is markedly reduced.

TRPV2 in Cancer

TRPV2 is a calcium-permeable channel regulated by growth factors including insulin-like growth factor, epidermal growth factor, and platelet-derived growth factor (Kanzaki et al. 1999). Given that calcium entry is required for promotion of cell growth induced by these growth factors, it is not surprising that TRPV2 is one of the key molecules regulating proliferation of cancer cells. In this regard, the expression of TRPV2 is upregulated in certain types of cancer cells. In bladder cancer, the expression of TRPV2 is upregulated. Caprodossi et al. (2008) reported that, in specimens of human bladder cancer, TRPV2 is expressed abundantly. Their results showed that the higher the expression of TRPV2, the higher the grade of malignancy was. Furthermore, poorly differentiated cells express a higher amount of TRPV2, consistent with the idea that TRPV2 modulates growth of cancer cells (Yamada et al. 2010). TRPV2 is also expressed in prostatic cancer. Especially, the expression levels of TRPV2 were particularly higher in patients with metastatic cancer (Monet et al. 2010). In accordance with this notion, lysophospholipids such as lysophosphatidylcholine and lysophosphatidylinositol induce translocation of TRPV2 to the plasma membrane and thereby increase cytoplasmic [Ca2+] in prostatic cancer cells (Monet et al. 2009). In addition, activation of this channel promotes migration of the prostatic cancer cells, and, conversely, inhibition of TRPV2 translocation attenuates migration. These results suggest that TRPV2 is critical for migration of prostatic cancer cells. Since TRPV2 is important for promotion of cell growth, TRPV2 is involved in the regulation of growth and migration of prostatic cancer cells.

Summary

TRPV2 is a calcium-permeable cation channel structurally related to TRPV1, the capsaicin receptor. Various ligands including growth factors activate PI 3-kinase and induce translocation of TRPV2 from ER to the plasma membrane. Upon removal of the ligands, TRPV2 is internalized gradually and accumulates in ER. Mechanical stresses also activate PI 3-kinase and induce translocation of TRPV2. Hence, TRPV2 functions as a mechanosensitive channel. TRPV2 is expressed ubiquitously, and the expression is high in certain types of cells and tissues including neurons, neuroendocrine cells, vascular smooth muscle cells, endothelial cells, cardiomyocytes, macrophages, lymphocytes, oral mucosa, and urothelium. TRPV2 modulates cell growth, differentiation, secretion, muscle contraction, migration, phagocytosis, and gene expression. TRPV2 is abundantly expressed in certain type of cancer and is involved in growth and migration of cancer cells.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Cell Biology, Institute for Molecular & Cellular RegulationGunma UniversityMaebashiJapan