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Introduction to TRPV2 Receptors

Transient receptor potential vanilloid type 2, TRPV2, is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions. TRPV2 channel has a similar structure to potassium channels, which are the largest ion channel family. This channel is composed of six transmembrane spanning regions (S1-S6) with a pore forming loop between S5 and S6 . The pore forming loop also defines the selectivity filter, which determines the ions that are able to enter the channel. The S1-S4 region as well as the N and C terminal of the protein is important in reference to the gating of the channel. Although TRPV2 is a nonspecific cation channel, it is more permeable to calcium ions; calcium is an intracellular messenger and plays a very important for a variety of different cellular processes. At rest, the pore channel is closed; in the activated state, these channel opens, allowing the influx of sodium and calcium ions that initiates an action potential.

Protein TRPV2 PDB 2f37

The vanilloid TRP subfamily (TRPV) named after the vanilloid receptor 1 consist of six members, four of them (TRPV1-TRPV-4) have been related to thermal sensation. TRPV2 shares 50% of its homology with TRPV1. Compared to TRPV1 channels, TRPV2 channels do not open in response to vallinoids like capsaicin or thermal stimuli around 43°C . This may be due to the composition of the ankyrin repeat domains in TRPV2, which are different than those in TRPV1. However, TRPV2 channels can open by noxious temperatures greater than 52°C . TRPV2 initially was characterized as a noxious heat sensor channel, but more evidence suggest its importance in various osmosensory and mechanosensory mechanisms. The channel can open in response to a variety of stimuli including hormones, growth factors, mechanical stretching, heat, osmotic swelling, lysophospholipids and cannabinoids (SITE).These channels are expressed in medium to large diameter neurons, motor neurons, and other non- neuronal tissues like the heart and lungs, which indicates its versatile function. The channels has an important role for basic cell function including contraction, cell proliferation, and cell death. The same channel can have different functions depending on the type of tissue. Other roles of TRPV2 continue to be explored in an attempt to define the role of translocation of TRPV2 by growth factors.”

TRPV2 was independently discovered by two research groups and described in 1999. It was identified in the lab of David Julius as a close homolog of TRPV1, the first identified thermosensitive ion channel.[5] The group of Itaru Kojima from Gunma University was looking for a protein which is responsible for the entry of calcium into cells in response to insulin-like growth factor-1 (IGF-1). Upon stimulation of cells with IGF-1 TRPV2 translocates towards and integrates into the cell membrane and increases intracellular calcium concentrations.[8] (May need to edit a bit and check references) (From Wikipage)

Homology of Different Species

Orthologoues between rat and mouse aligned with humans

The TRPV subfamily of channels of 1 through 4 have unique functions. One important variation is that these channels trigger cellular signaling pathways via non-selective cation flux, which makes them unique. Specifically, the TRPV 2 channel has structural similarities among each other. For instance, the channel comprises of six transmembrane segments and a pore forming loop between S5 & S6. Among the Homo- species genome, putative homologs can be found. This suggests that the amino acids and proteins coded come from a common ancestor where their structures are conserved in function.

Among the subfamily, TRPV2 and TRPV1 share 50% of their sequence identity of not only in humans, but in rats as well. The rat TRPV2 can be comparable to that of humans because they exhibit similar surface localization among one another. Each channel possesses ATP binding regions and the 50% suggests that both channel’s ARD (Ankyrin repeat domain) bind to different regulatory ligands as well. TRPV2 is majorly in a subpopulation of medium to large sensory neurons, as well as being distributed in the brain and spinal cord. The mRNA expression of TRPV2 is also found in human pulmonary and umbilical vein endothelial cells. 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. In circulatory organs, studies and data suggest that TRPV2 may be a mechanosensor, meaning that it can sense external stimuli; the mechanisms involved in opening TRPV2 by membrane stretching or hypoosmotic cell swelling have not yet been determined.

Mus Musculus

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. 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, showing that TRPV2 plays a role in mechanotransduction in mice as well. 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.

Rattus Norvegicus

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.

TRPV2 Interactions in Humans

Cancer

The cells that make up our body takes in nutrients to perform specific jobs and removes waste via blood vessels. During maturation cells divide and proliferate keep up with the increased demands of our body. This processes of cell division is tightly regulated to prevent aberrant proliferation. If these regulatory proteins are mutated, cells may divide uncontrollably which results in cancer. TRPV2 plays a role in negative homeostatic control of excess cell proliferation by inducing apoptosis (programmed cell death). This is accomplished predominantly through the Fas pathway (also known as the death-inducing signaling complex). Activation of TRPV2 by growth factors and hormones induce the receptor to translocate from intracellular compartments to the plasma membrane, which initiates the development of death signals. 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.

TRV2 channels also play a role in the formation maintenance of cancerous cells in the body. 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. TRPV2 is also expressed in t24 cells, which are urinary bladder cancer cells. TRPV2 has also proven to negatively affect glioma cell survival. TRPV2 in these cells leads to resistant to apoptotic cell death, leading to harmful, carcinogenic cell survival (Nabissi et al., 2010). Beyond the various types of cancer TRPV2 is involved in, TRPV2 is also a key component affecting muscular dystrophy. “TRPV2 is a principal Ca2+ entry route leading to sustained intracellular calcium increase and muscle degeneration.”

Role in Immunity

Antigens presentation

TRPV2 is express 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. The influx of calcium seems to play an important role in these functions. Immune cells 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. 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) (Pic?) The region between the MHC-peptide and the T cell receptor is known as the immunosynapse. TRPV2 are highly concentrated in this region. When these two cells interact, it allows calcium diffuses through the TRPV2 channel. Thus, TRPV2 is involved in T cell activation and proliferation. Abnormal TRPV2 expression has been reported in hematological diseases including multiple myeloma, myelodysplastic syndrome, Burkitt lymphoma, and acute myeloid leukemia .

TRPV2 in Mast Cells

Mast cells are a type of white blood cell rich in histamine. They 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 TRPV2 protein subunits along with coupling of these proteins to calcium and proinflammatory degranulation have been found in mast cells. TRPV2 is activated in high temperatures (over 50°C) which permits calcium ion influx, inducing release of proinflammatory factors (degranulation). Therefore, TRPV2 is essential in mast cell degranulation as a result of its response to heat

TRPV2 in T and B Lymphocytes

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. Thus, the knockdown of TRPV2 in T cells disturbs T cell receptor signaling. It also acts as a transmembrane protein on the surface of B cells, negatively controlling B cell activation.

Endocrine

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, which is a molecule that functions to keep glucose levels low. Under unstimulated conditions, TRPV2 is localized in the cytoplasm. Activation cause the channel to translocate to the plasma membrane. This triggers the influx of calcium resulting in insulin secretion

Heart

TRPV2 is very important in the structure and function of cardiomyocytes (heart cells). Compared to skeletal muscles, TRPV2 is expressed 10 folds higher in cardiomyocytes 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 disc 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.

Neurology

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), which has been researched for its positive effects in the treatment of epilepsy (seizures). CBD is able to bind to TRPV2 (as only plant-derived cannabinoids are TRPV2 agonists), reducing epileptic activity and decreasing mortality as a result. Recent research demonstrated how CBD, in vitro, decreased epileptiform local field potential burst amplitude and burst duration while increasing burst frequency. Testing CBD in vivo resulted in the decrease of 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.