Function
is a non-selective cation channel in eukaryotic membranes involved in detecting noxious chemicals and high temperatures. TRPV1 is a ligand activated channel that controls the proton concentration associated with intracellular acidosis. TRPV1 is known to be activated by many stimuli, but is most notably known for activation by capsaicin found in hot chili peppers, temperatures greater than 43℃, and pH changes. Activation of TRPV1 triggers inflammation, hyperalgesia, and a burning sensation. TRPV1 is most commonly expressed in the skin and nerves as well as a few other sensitive tissues. TRPV1 is composed of many responsible for the redox sensing that causes the inflammation and hyperalgesia responses.[1]
Structure
The exact structures of TRPV1 are difficult to obtain because of the conformational uniformity required to perform X-ray crystallography. This makes it exceedingly difficult to observe the conformational states of the channel in the presence and absence of stimuli. However, can show its conformation upon activation. It is known that TRPV1 is a homotetramer that has a similar structure to a voltage-gated ion channel. Phosphoinositide-interacting protein (PIRT) is an important regulatory subunit of TRPV1 responsible for activation of the channel. Positive regulation of the TRPV1 channel can be controlled by the binding of PIRT and phosphatidylinositol 4,5-bisphosphate (PIP2). [2]
Sensitization
TRPV1 can undergo sensitization, meaning that its sensitivity to stimuli can be increased by prolonged exposure. Many inflammatory mediators including prostaglandins and bradykinin are released after the initial inflammation from TRPV1 activation occurs. These inflammatory mediators will increase the sensitivity to the stimuli causing the compounding effect known as hyperalgesia. It can also in turn cause allodynia which is a painful response to stimuli that are not pain inducing. The sensitization of TRPV1 is thought to be connected to phosphorylation by protein kinase C and the cleavage of PIP2.[3]
Desensitization
TRPV1 can also undergo desensitization after prolonged and repeated exposure to the stimulus capsaicin. An increase of extracellular calcium entering the cell and changing the concentration is thought to be the reason desensitization occurs. The calcium ions will displace ATP leading to a desensitization of the channel. A decrease of PIP2 levels may also be associated with desensitization since PIP2 is known to inhibit desensitization. Capsaicin is known to have analgesic, pain relieving, effects which may be due to the desensitization of TRPV1 that it causes. This is an area of interest for pharmacology because of its potential to progress future drug development.[4]
Pharmaceutical Significance
The pharmaceutical field has an interest in TRPV1 in regards to its temperature activation specifically. If TRPV1 can be desensitized or blocked, it would be a great development for a drug used to control pain of burns. However, with TRPV1 blocked there are adverse effects because it is important to temperature regulation. Temperature regulation is vital for survival, so without the TRPV1 heat activation many issues could potentially arise. Antagonists that block TRPV1 are being identified in an effort to develop pain reducers. TRPV1 has known competitive and non-competitive antagonists that block its function. Capsazepine is a competitive antagonist of TRPV1 and ruthenium red is a non-competitive antagonist of TRPV1. Antagonists of TRPV1 often result in lowering body temperature due to the lack of temperature regulation. Agonists of TRPV1 will result in the increase of body temperature, which is one of the bodily responses commonly observed when consuming capsaicin because of its role as a TRPV1 agonist.[5]
See also: