Focus+on+the+TRPV1+Gene


 * The Gene Expressed: The TRPV1 Protein Channel**

The protein that arises from the TRPV1 gene is Q8NER1-TRPV1_HUMAN, otherwise known as Transient Receptor Potential Cation Channel Subfamily V member 1. This protein has a quaternary structure, weighs in at 839 amino acids, and has a molecular mass of 94956 Da. It responds to heat and low pH, and interacts with PIRT, TRPV3, CALM, PRKCM, CSK, PRKDG, NTRK1, and TMEM100.

The TRPV1 protein is a channel belonging to the TRP family of channels. Transient receptor potential (TRP) channels make possible the experience of sensation, temperature, and pain. They are found in many body tissues and cells. Various chemical and environment signals activate TRP channels, changing their membrane potential and allowing ions to cross over into cells. Consequently, TRP channels play a fundamental role in essential life processes. Abnormalities in TRP channels can lead to serious cell dysfunction. To date, twenty-three TRP channels have been identified (Figure 1). They are categorized according to subfamilies: TRPC, TROM, TRPA, TRPML, TRPP, and the subfamily of interest here, TRPV. These subfamilies are distinguished by sequence similarity, rather than function. Hence, subfamily members may act quite differently or show sensitivity to very different stimuli. TRPC, TRPV, TRPM, and TRPA, for example, are highly temperature sensitive, while TRPM2, TRPM6, and TRPM7 are involved in enzymatic processes. Some subfamilies interact and form complexes of their own.



**Transient receptor potential (TRP) channel subfamilies. The subunit topology is shown with highlights**
 * of specific functional domains. Subunits known to co-assemble are indicated by lines. (Zheng, 2013) **

Looking more closely, at the TRPV subfamily (above figure), we can discern six members: TRPV1 to TRPV6. These members can be further broken down into two classes: TRPV1 to TRPV4 (Ca2+ cation channels that are heat sensitive) and TRPV5 to TRPV6 (Ca2+ cation channels that are not heat sensitive). Our interest here is the TRPV1 channel because of its role in pain sensitivity.

Pain perception is the result of neural signals that start in terminal nociceptors and then travel to second-order neurons in the spinal cord or brainstem. From there, these signals travel to the higher order brain areas. In this process, molecular mechanisms are at work, many being activated by ion channel pathways. TRP channels are among these pathways, and of these, the TRPV1 is especially implicated. TRPV1 has been of interest to researchers because of its sensitivity to capsaicin, a compound present in chili paper. The “V” of TRPV comes from the word “vallinoid,” the molecular compound that makes capsaicin taste hot. Studies have shown that inhibition of the TRPV1 channel can reduce pain (Kosek et al.). As a result, the TRPV1 channel is of interest in pharmaceutical research into analgesic drugs.

TRP channels are many and diverse, impacting almost every organ of the body. Similar in kind to voltage-gated potassium and sodium channels, they respond to a variety of chemical and physical stimuli. They are implicit in sensation and the adsorption of calcium. The vanilloid receptor family, designated by “TRPV,” is a member of the TRP family. TRPV channels are Ca2+-permeable cation channels that regulate such diverse functions as gene transcription, cell movement, muscle contraction and sensory transduction. There are six members in the TRVP family with TRVP1 being the most scrutinized for fibromyalgia because of its sensitivity to endogenous and exogenous vanilloids and its role as a membrane channel (Zheng, 2013).

TRPV1 has been shown to be a major factor in pain sensitivity and, as such, has been a major focus for the development of analgesic drugs. At a basic level, TRPV1 receptors are activated by vanilloids like that in capsaicin in such a way that incoming calcium and sodium depolarize the cell, thereby passing on a pain signal. But many other elements are involved in pain sensation. Pain transduction can be enhanced by an acidic extracellular pH caused by ischemia or inflammation. Inflammation’s attendant agents such as bradykinin, serotonin, histamine, and prostaglandins also stimulate TRPV1 thanks to the activation of a PKA-dependent pathway that influences capsaicin-sensitive responses. Hence, PKA plays an important role in hyperalgesia. Inflammation also leads to a “downstream” event in which TRPV1 is phosphorylated by PKA and, again, capsaicin sensitivity transduces pain signals. In sum, three different kinases are implicated in TRPV1 activity. To these pathways can be added lipid regulating functions, the role of temperature in inducing TRPV1 channel action, and the transduction action of Ad and C-fibers (Rosenbaum, 2007).