Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2)
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
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.
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.
- Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Zing Y, Lubischer JL, Kreig PL, Krupenko SA, Thompson WJ, Barres BA. A transcriptome database for astrocytes, neuron, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci. 2008;28:264–78.PubMedCrossRefGoogle Scholar
- Caprodossi S, Lucciarini R, Amantini C, Nabbisi M, Canesin G, Ballarini P, Di Spilimbergo A, Cardarelli MS, Servi L, Mammana G, Santoni G. Transient receptor potential vanilloid type 2 (TRPV2) expression in normal urothelium and urothelial carcinoma of human bladder: correlation with the pathologic state. Eur Urol. 2008;54:612–20.PubMedCrossRefGoogle Scholar
- Hamamoto Y, Takumida M, Hirakuwa K, Tatsukawa T, Ishibashi T. Localization of transient receptor potential vanilloid (TRPV) in the human larynx. Acta Otolaryngol. 2008;129:495–507.Google Scholar
- Koch SE, Gao XQ, Haar L, Jiang M, Lasko VM, Robbins M, Cai W, Brokamp C, Varma P, Trabter M, Liu Y, Ren XP, Lorenz JN, Wang HS, Jones WK, Rubinstein J. Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation. J Mol Cell Cardiol. 2012;53:134–44.PubMedPubMedCentralCrossRefGoogle Scholar
- Monet M, Lehen’kyi V, Gackiere F, Firlej V, Vandenberghe M, Rassendren F, Roudbaraki M, Gkira D, Pourtier A, Bidaux G, Slomianny C, Humez S, Prevarsakaya N. Role of cationic channel TRPV2 in promoting prostatic cancer migration and progression to androgen resistance. Cancer Res. 2010;70:1225–35.PubMedCrossRefGoogle Scholar
- Yamada T, Ueda T, Shibata Y, Ikegami Y, Saito M, Ishida Y, Ugawa S, Kohri K, Shimada S. TRPV2 activation induces apoptotic cell death in human T-24 bladder cancer cells. Urology. 2010;76(509):e1–e17.Google Scholar