Trp

Introduction

Trp is a multigene family encoding an integral membrane protein functioning as ion channels. Trp members are conserved in vertebrates, invertebrates and even in the yeast. The trp family can be divided into seven subfamilies: TRPC (canonical), TRPP (polycystin), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), TRPN (NOMPC-like) and TRPV (vanilloid). Trps are involved in various psychological processes like the sensation of different stimuli or homeostasis. This family of ion channels shows a variety of gating mechanisms. The trp ion channels are important for cellular regulation as they cause depolarisation and repolarisation of the cellular membrane affecting ion concentration and intracellular activities. 

Trp and its Evolutionary History

Trp genes were first described in Drosophila melanogaster. Transient receptor potential was a mutant fruit fly that showed the transient response to steady light instead of sustained electroretinogram, which was recorded in the wild types. In 1989, Rubin and Montell identified the trp gene. Studying its resemblance to other cation channels, the product of the trp gene was proposed to study further. Currently, more than 100 types of trp genes have been identified in different vertebrates, invertebrates and yeasts. Human Trp varies in length and range between 911 to 11.4 kb. The regulators of the trp genes are yet to be identified.

Trp and its Mechanism

Trp or transient receptor potential gene encodes integral membrane protein functioning as ion channels. Trp biochemistry is very interesting. Its protein functions as a homotetramer. It constitutes six transmembrane segments from S1 to S6 with a loop between the S5 and S6. The loop is also defined as a reentrant loop.  A variety of mechanisms can regulate the activity of the transient receptor potential. Some of the mechanisms and their relevance are listed below:

• Membrane Voltage: Most Trps are naturally voltage-dependent, and their activation is very sensitive. Lysine and arginine are the major molecular counterparts involved and lie in the transmembrane section of S4 and linker between S4-S5. 
• Phosphorylation and Dephosphorylation: The activation of Protein Kinase C or PKC results in downregulation of the Trps. When PKC is activated, it dephosphorylated Trp like TRPM8 and subsequently inactivated the channels. Again the activation of another protein, PKA or Protein Kinase A, has the opposite effect on another Trp, TRPV1. TRPV1 is activated when PKA phosphorylates it.
•  Membrane Phospholipid: The membrane phospholipids directly affect the activity and regulation of transient receptor potential. PtdIns(4,5)P2  or Phosphatidylinositol 4,5-bisphosphate affects the function of Trp either directly or indirectly. When the level of Phosphatidylinositol 4,5-bisphosphate falls, the activity of Trp channels falls subsequently.
• Ligands: Many exogenous and endogenous ligands are involved in the modulating transient receptor potential channel activity. A classic example under the criteria is the temperature-sensitive TRPV1 channel, which structurally unrelated botanical compounds can activate like piperine and camphor compounds. 

Trp functions and localisation

Trps are expressed in almost all cells, including excited and non-excited cells. Trps are localised in the cellular membranes except for the nuclear membrane and mitochondria. It localises especially in the plasma membranes. The major function of  transient receptor potential is:

• Essential for sensory functions like taste transduction and pheromone signalling.
• The influx of ions like Ca+2 and Mg+2  helps balance the driving force of ion entry. 
• Has homeostatic functions like osmoregulation and reabsorption
• It also helps in motile functions like vasomotor control and muscle contraction. 

Diseases due to Trps

Channelopathies are a category of diseases caused by the malfunctioning of ion channels or interacting proteins or their subunits. Several Trp genes are involved in a wide range of human diseases. The disease can be caused due to various reasons when the trp biochemistry is hampered. A gene mutation, impaired channels’ functioning, autoimmunity or acquired mechanisms can cause the diseases. A list of human Trp diseases is mentioned.

• TRPV4: This is an inherited disease related to the disorder of bone growth.
• TRPC6: This is related to progressive kidney failure and proteinuria. It affects the permeability of the glomeruli.
• TRPM4: This disease is caused due to mutation of the gene causing heart blockage type 1.
• TRPM1: The mutation in the TRPM1 gene causes retinal disorder followed by loss of function of rod and cone cells.
• TRPM6: It is caused due to autosomal recessive disorder causing secondary hypocalcemia and hypomagnesemia.
• TRPML1: It is also an autosomal recessive disorder related to the nervous system. It causes psychomotor retardation, failure of the corpus callosum, blood iron deficiency, etc.
• TRPA1: It is known to cause upper body episodic pain caused due to physical stress or fasting.

Conclusion

From discovering the first transient receptor potential fruitfly to more than 100 trp genes in the animal kingdom, scientists’ importance and views on the Trp genes and proteins. Trp proteins have become important to understand various sensory and physiological processes. Studying the mechanisms and the change of action has concluded the treatment and reason of various diseases related to trp in humans. Still, many mechanisms are yet to be studied to resolve further sensitisation and desensitisation. The research is ongoing to help us better understand the role of transient receptor potential to avoid related diseases.