TRPV2

In homo sapiens, there is broad expression of TRPV2 in the lymph nodes, spleen, lung, appendix, and placenta; it is mostly expressed in the lungs.[10] TRPV2 is majorly in a sub population of medium to large sensory neurons, as well as being distributed in the brain and spinal cord.[11] The mRNA expression of TRPV2 is also found in human pulmonary and umbilical vein endothelial cells.[11] Based on mRNA expression of TRPV2 in mice, it is also speculated that it is expressed in arterial muscle cells, which can then be influenced by blood pressure; though it was evident that TRPV2 expression was localized in the intracellular area, some growth factors localized it to the plasma cell membrane.[11] In circulatory organs, studies and data suggest that TRPV2 may be a mechanosensor, meaning that it can sense changes in external stimuli; the mechanisms involved in opening TRPV2 by membrane stretching or hypoosmotic cell swelling have not yet been determined.[11]

Mus Musculus-huismuis2

In mus musculus (house mouse), TRPV2 functions as a protein coding gene. There is broad expression of TRPV2 in the thymus, placenta, cerebellum, and spleen; it is most commonly expressed in the thymus.[12] The thymus is a lymphoid organ involved in the function of the immune system, where T cells mature. T cells are an important component to the adaptive immune system, because it is where the body adapts to foreign substances; this demonstrates TRPV2’s importance in the immune system. TRPV2 in mus musculus is also activated by hypo-osmolarity and cell stretching, indicating that TRPV2 plays a role in mechanotransduction in mice as well.[12] In experiments with knockout mice (TRPV2KO mice), it was found that TRPV2 is expressed in brown adipocytes and in brown adipose tissue (BAT). It can be concluded that TRPV2 plays a role in BAT thermogenesis in mice, since it was found that a lack of TRPV2 impairs this thermogenesis in BAT; given these results, this could be a target for human obesity therapy.[13]

In rattus norvegicus (Norway rat), there is broad expression of TRPV2 in the adrenal glands and the lungs, being most present in the adrenal glands. TRPV2 is also present in the thymus and spleen, but not in high amounts. Without using any external growth factors, TRPV2 is highly specific to the plasma cell membrane in rat adult dorsal root ganglions, cerebral cortex, and arterial muscle cells.[11]

TRPV2 plays a role in negative homeostatic control of excess cell proliferation by inducing apoptosis (programmed cell death).[9] This is accomplished predominantly through the Fas pathway, also known as the death-inducing signaling complex. Activation of TRPV2 by growth factors and hormones induces the receptor to translocate from intracellular compartments to the plasma membrane, which initiates the development of death signals.[14] An example of the role of TRPV2 in apoptosis is its expression in the bladder cancer t24 cell line. TRPV2 in bladder cancer leads to apoptosis through the influx of calcium ions through the TPRV2 channel. In some tumors, the over-expression of TRPV2 can lead to abnormal signaling pathways that drives unchecked cell proliferation and resistance to apoptotic stimuli. The over-expression of TRPV2 has been linked to several cancer types and cell lines. TRPV2 is expressed in human HepG2 cells, a cell line containing human liver carcinogenic cells. Heat allows for calcium entry into these cells through TRPV2 channels, which aid in the maintenance of these cells.[15] TRPV2 also negatively affects patients with gliomas. TRPV2 in carcinogenic glial cells leads to resistance to apoptotic cell death, leading to harmful, carcinogenic cell survival.[16]

Antigens presentation

TRPV2 is expressed in the spleen, lymphocytes, and myeloid cells including granulocytes, macrophages and mast cells. Among these cell types, TRPV2 mediates cytokine release, phagocytosis, endocytosis, podosome assembly, and inflammation.[17] The influx of calcium seems to play an important role in these functions. Mast cells are leukocytes (white blood cells) rich in histamine which are able to respond to a variety of stimuli, often initiating inflammatory and/or allergic responses. The responses generated by mast cells rely on the calcium influx in the plasma membrane with the help of channels. Surface localization of the TRPV2 protein along with coupling of the protein to calcium and proinflammatory degranulation have been found in mast cells. The activation of TRPV2 in high temperatures permits calcium ion influx, inducing the release of proinflammatory factors. Therefore, TRPV2 is essential in mast cell degranulation as a result of its response to heat.[18] Immune cells are also able to kill pathogens by binding to them and engulfing them in a process known as phagocytosis. In macrophages TRPV2 recruitment toward the phagosome is regulated by PI3k signaling, protein kinase C, akt kinase, and Src kinases.[9] They are able to locate these microbes through chemotaxis which is TRPV2 mediated. When the pathogen is endocytosed it is degraded then presented on the membrane of antigen presenting cells (i.e macrophages). Macrophages present these antigens to T cells via a major histocompatibility complex (MHC). The region between the MHC-peptide and the T cell receptor is known as the immunosynapse. TRPV2 channels are highly concentrated in this region. When these two cells interact, it allows calcium to diffuse through the TRPV2 channel. TRPV2 mRNA has been detected in CD4+ and CD8+ T cells as well as in human B lymphocytes. TRPV2 is one type of ion channel that directs T cell activation, proliferation, and defense mechanisms. If the TRPV2 channel were absent or not functioning properly in T cells, T cell receptor signaling would not be optimal. TRPV2 also acts as a transmembrane protein on the surface of B cells, negatively controlling B cell activation.[18] Abnormal TRPV2 expression has been reported in hematological diseases including multiple myeloma, myelodysplastic syndrome, Burkitt lymphoma, and acute myeloid leukemia.[17]

TRPV2 seems to be essential in glucose homeostasis. It is highly expressed in MIN6 cells, which is a β-cell. These cell types are known for releasing insulin, a molecule that functions to keep glucose levels low. Under unstimulated conditions, TRPV2 is localized in the cytoplasm. Activation causes the channel to translocate to the plasma membrane. This triggers the influx of calcium resulting in insulin secretion.[7]

TRPV2 is very important in the structure and function of cardiomyocytes (heart cells). Compared to skeletal muscles, TRPV2 is expressed 10 times as high in cardiomyocytes[19] and is important in current conduction. TRPV2 has been shown to be involved in stretch-dependent responses in heart cells. TRPV2 expression is concentrated in intercalated discs which allows the synchronous contraction of cardiomyocytes. Abnormal expression of TRPV2 results in reduced shortening length, shortening rate, and lengthening rate which ultimately compromise cardiac contractile function.

The cannabis constituent, cannabidiol (CBD), is a compound that acts in the release of neurotransmitters in the brain (part of the class of chemicals called cannabinoids) and has been researched for its positive effects in the treatment of epilepsy. CBD is able to bind to TRPV2 (as only plant-derived cannabinoids are TRPV2 agonists),[20] which results in a reduction of epileptic activity and, consequently, a decrease in mortality. Recent research demonstrated that, in vitro, CBD decreases epileptiform local field potential burst amplitude and burst duration and increases burst frequency. Testing CBD in vivo indicated a decrease in severe seizure incidence (an increase in anticonvulsant effects). Therefore, CBD increases the expression and activation of TRPV2, resulting in the inhibition of epileptic activity both in vitro and in vivo.[21]