TRP super family ion channels: A review

Introduction

The transient receptor potential (TRP) super family first identified by Cosens and Manning (1969) [5] and named as "TRP" by Minke et al. (1975) [20] is a large protein family that is multimodal ion channel widely distributed in animal tissues with variety of roles to play (Zhang et al., 2023) [34] . The nomenclature as "TRP" was on the basis of its electrophysiological phenotype that oscillates between Ca 2+ transporting and non-transporting states (transient state). In mammals, it comprises of atleast six subfamilies viz; TRPC (canonical), TRPM (melastatin), TRPP (polycystins), TRPA (ankyrin), TRPML (mucopolin) and TRPV (vanilloid) (Montell et al., 2002) [22] . TRP channels have six transmembrane spanning domains (S1-S6), with a pore-forming loop between S5 and S6, and both the C and N termini are located intracellularly (Wu et al., 2010) [30] .

Classification of TRP channels

In mammals, based on amino acid sequence and topological differences, it has been divided into two groups viz; group 1 and group 2. Group 1 with four subfamily members (TRPC, TRPV, TRPM and TRPA), and group 2 with two subfamilies (TRPP and TRPML) of seven subfamilies have multiple roles in animal body.

TRPC (canonical)

These channels are first to be identified in TRP family. These are non-selective cation channels (Feng, 2017) [8] with a molecular weight ranging from ten to few hundred kilodaltons (Latorre et al., 2009) [16] . Based on amino acid sequence, seven TRPC proteins (1-7) have been identified till date (Montell et al., 2002) [22] . They have a wide distribution in animal tissue and involved in various functions like receptor-activated Ca 2+ entry, increase intracellular Ca 2+ level, smooth muscle contraction, endothelial cell function, neuron differentiation and also act as sensors for mechanical stretch in vasculature and oxidative stress.

TRPV (vanilloid)

The TRPV subfamily can be divided into 4 groups: TRPV1/2, TRPV3, TRPV4, and TRPV5/6. TRPV1 to TRPV4 are non-selective cation channels that can be activated by a number of different stimuli, such as second-messenger binding, heat and cold, and chemical and/or mechanical stress. These channels are modestly permeable for Ca, whereas the other 2 members of the family, TRPV5 and TRPV6, are highly selective for Ca and tightly regulated by intracellular Ca 2+ concentration (Vanoevelen et al., 2011) [27] . TRPV5 and TRPV6 share about 75% homology at the amino acid level.

The main sequence differences are located in the N-and Cterminal tails. TRPV5 and TRPV6 reveal only 30-40% homology with other members of the TRP family, and possess unique properties that distinguish them from other TRP channels in that they have a constitutively activated Ca 2+ permeability at physiological membrane potentials while other TRP channels need activation by receptor stimulation. In general TRPV5 is the major isoform in kidneys, whereas TRPV6 is highly expressed in the small intestine (Dekker et al., 2003) [6] .

TRPM (melastatin)

It is the largest member of TRP super family and consists of eight members (1-8). They are involved in numerous physiological functions like cell proliferation, temperature sensing, development of blood vessels, cancer progression, neurological disorders, endothelial dysfunction, type-II diabetes, etc. (Zhang et al., 2023) [34] .

TRPA (ankyrin)

TRPA consists of only one member (1) with numerous Nterminal ankyrin repeats. TRPA1 is a sensor for diverse noxious external stimuli such as intense cold, irritating compounds, mechanical stimuli, reactive chemicals, and endogenous signals associated with cellular damage (Naert et al., 2021) [23] . It is heavily linked to chronic pain, neuropathic pain, migraine, asthma, and respiratory inflammation.

TRPP (polycystins)

It the most primitive type and consists of three members (TRPP2, TRPP3 and TRPP5) and act as non-selective Ca 2+ permeable cation channels. TRPPs act as sensors for external mechanical forces, such as fluid shear stress in the renal tubule, involved in osteogenesis and preventing bone loss. Mutation in the protein leads to PCKD (Polycystic kidney disease) leading to formation of fluid filled cysts in the kidney (Li, 2017) [17] .

TRPML (mucopolin)

It includes three members (1-3). They are non-selective cation channels and are involved in lysosomal acidification, membrane trafficking, autophagy, and lysosomal exocytosis, chemokine secretion, modulates inflammatory responses, hair cell function in the cochlea and melanocytes (Flores and Garcia, 2011) [9] .

Effects of TRP channels on organ systems

Several factors are responsible for activation and inhibition of TRP channels in animal body like heat or cold stimuli, changes in osmolarity, proton gradients, noxious and irritant compounds, several natural products, herbs and compounds of plant origin (Vincent and Duncton, 2011) [29] . Based on the agonist and antagonist activity, some compounds have also been used in clinical trials and drug designing to treat certain diseases either by inhibiting or activating the expression patterns of TRP channels. These channels are widely distributed throughout the organ systems with unique effects.

Nervous system: TRP channels are widely distributed in the neuronal and neuroglial cells of the brain and are involved in regulating various neurological disorders. Activation of TRPC1, TRPC3 and TRPC4 and down regulation of TRPC5 helps in neuron protection (Kim et al., 2006) Activation of TRPV6 reduces the risk of hemorrhagic stroke, neuronal death and survival in ischemic stroke and reduces neurotoxicity and apoptosis by increasing the Ca 2+ influx (Huang, 2017) [11] . TRPV1 regulate the microglia and enhance autophagy and phagocytosis. Activation of TRPV2 induces the release of nerve growth factor (NGF) and regulated blood-brain barrier (BBB) function, which may be associated with ischemic stroke (Lu et al., 2019) [18] . TRPV4 alleviates ischemic injury by increasing glutamate and overloading Ca 2+ , thereby reducing neurotoxicity. The TRP channel may represent a promising therapeutic strategy for neurological disorders with special emphasis on the TRPC channel because it is more widely distributed in the nervous system.

Respiratory system: TRP channels are widely distributed in the lungs and hence can be targeted for treatment of respiratory disorders. It has been reported that in cough (a reflex mechanism to clear the upper airways), TRPV1 channels are mostly involved. Therefore; inhibition of TRPV1 expression can minimize the cough symptoms (Anderson, 2004) [2] . Use of TRPV1 and TRPV6 antagonists can reduce the symptoms of asthma as arachidonic acid is released in lungs during asthma attacks and have a stimulatory effect on TRPV1 (Hwang et al., 2000) [12] . Rahaman et al. (2014) [24] reported that TRPV4 activity was up-regulated in lung fibroblasts in lung fibrosis. TRPV4 also plays an important role in the formation of pulmonary edema and acute lung injury.

Cardiovascular system: Vasoconstriction leads to hypertension in patients with cardiovascular disorders. It has been reported that activation of TRPV1 channels can reduce vasoconstriction by inducing the release CGRP (Calcitonin Gene-Related Peptide) leading to potent vasodilatation (Zygmunt et al., 1999) [36] . TRPV4 and TRPM4 have also been reported to have regulatory effects on systemic blood pressure suggesting their vasoprotective effect (Earley et al., 2009) [7] . Uro-genital system: TRPC6 is expressed in glomerular podocytes and its up-regulation may lead to certain kidney disease like glomerulosclerosis and membranous nephropathies (Moller et al., 2007) [21] . TRPV1 is highly expressed in lining epithelium of the urinary bladder in patients with bladder disorders (Zhang et al., 2015) [33] .

Digestive system: It has been reported that activation of TRPV4 receptors in the GI tract can trigger inflammation. Inflammation in mouse colitis models can be alleviated by the activation of TRPM8 as reported by Vergnolle (2014) [28] . Activation of TRPV1 increases energy metabolism and prevents the accumulation of visceral fat (Ma et al., 2011). TRPV6 channels are actively involved in absorption of calcium from gut epithelium (Ranjan et al., 2020) [25] .

Integumentary system: On the skin, TRPs act as interesting pharmacological targets because they allow for topical treatment and may reduce the risk of severe harmful effects (Koivisto et al., 2022) [15] . TRP channels are widely expressed in various skin cell types, including keratinocytes, melanocytes, nerve endings, and immune cells (Ho and Lee, 2015) [10] . Their functions involve hair growth, wound healing, skin cell proliferation and differentiation, immunity, skin barrier function, skin inflammation and pruritis (Toth et al., 2014) [26] .

Endocrine system: TRP channels have been expressed in a number of cancers like prostate cancer, breast cancer, colorectal and gastric cancers as these TRP channels play a role in tumor cell growth and proliferation (Zeng et al., 2010) [32] . TRP channels have also been reported to be expressed in adipose tissues and reduce obesity by increasing thermo genesis (Yoneshiro and Saito, 2013) [31] . In diabetes, it has been observed that TRPC4 was up regulated and TRPC1 and TRPC6 was down regulated in blood vessels of diabetic patients (Chung et al., 2009) [4] . TRPV4 further, has been reported to influence the release of insulin from pancreatic beta cells (Billert et al., 2017) [3] . Musculo-skeletal system: Expression of TRPA1 has been reported in osteoarthritis and inflammation (Zsombok and Derbenev, 2016) [35] . These channels upon activation lead to influx of sodium and calcium ions that causes depolarization of nerve endings leading to propagation of pain stimulus. Koh et al. (2014) [14] reported that down regulation of TRPA1 expression reduced the development of mechanical, thermal, and cold sensitivity. Apart from this, TRPV1 coexpression has also been reported to contribute towards mediating acute and chronic pain modulated by inflammatory mediators (Abbas, 2020) [1] .

Conclusion

TRP ion channels have been reported to express in almost all the organ systems of the body influencing various physiological functions either by up-or down regulations. Hence, these ion channels have become a target structure for various drug trials. Drugs either in the form of agonist or antagonists are being used or under trial against various diseases. Selective application of drug molecules to act on the targeted ion channels are required to prevent any cross reaction against the activation of depression of multiple TRP channels.

References

1. Abbas MA. Modulation of TRPV1 channel function by natural products in the treatment of pain. Chem Biol Interact. 2020;330:109-178.
2. Anderson GP. TRPV1 and cough. Thorax. 2004;59:730-731.
3. Billert M, Skrzypski M, Sassek M, Szczepankiewicz D, Wojciechowicz T, Mergler S, et al. TRPV4 regulates insulin mRNA expression and INS-1E cell death via ERK1/2 and NO-dependent mechanisms. Cell Signal. 2017;35:242-249.
4. Chung AW, Yeung KA, Chum E, Okon EB, van Breemen C. Diabetes modulates capacitative calcium entry and expression of transient receptor potential canonical channels in human saphenous vein. Eur J Pharmacol. 2009;613:114-118.
5. Cosens DJ, Manning A. Abnormal electroretinogram from a Drosophila mutant. Nature. 1969;224:285-287.
6. Dekker ES, Hoenderop JG, Nilius B, Bindels RJM. The epithelial calcium channels, TRPV5 and TRPV6: from identification towards regulation. Cell Calcium. 2003;33:497-507.
7. Earley S, Pauyo T, Drapp R, Tavares MJ, Liedtke W, Brayden JE. TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure. Am J Physiol Heart Circ Physiol. 2009;297(3):H1096-H1102.
8. Feng S. TRPC channel structure and properties. Adv Exp Med Biol. 2017;976:9-23.
9. Flores EN, Garcia AJ. TRPML2 and the evolution of mucolipins. Adv Exp Med Biol. 2011;704:221-228.
10. Ho JC, Lee CH. TRP channels in skin: from physiological implications to clinical significances. Biophysics. 2015;11:17-24.
11. Huang J. TRPC channels and stroke. Adv Exp Med Biol. 2017;976:61-71.
12. Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, et al. Direct activation of capsaicin receptors by products of lipoxygenases. Proc Natl Acad Sci U S A. 2000;97(11):6155-6160.
13. Kim JH, Choi S, Jung JE, Roh EJ, Kim HJ. Capacitative Ca²⁺ entry is involved in regulating soluble amyloid precursor protein release. J Neurochem. 2006;97(1):245-254.
14. Koh WU, Choi SS, Lee JH, Lee SH, Lee SK, Lee YK, et al. Perineural pretreatment of bee venom attenuated allodynia. BMC Complement Altern Med. 2014;14:431.
15. Koivisto AP, Belvisi MG, Gaudet R, Szallasi A. Advances in TRP channel drug discovery. Nat Rev Drug Discov. 2022;21:41-59.
16. Latorre R, Zaelzer C, Brauchi S. Structure-functional intimacies of TRP channels. Q Rev Biophys. 2009;42:201-246.
17. Li H. TRP channel classification. Adv Exp Med Biol. 2017;976:1-8.
18. Lu J, Zhou W, Dou F, Wang C, Yu Z. TRPV1 sustains microglial metabolic reprogramming. EMBO Rep. 2021;22(6):e52013.
19. Ma L, Zhong J, Zhao Z, Luo Z, Ma S, Sun J, et al. Activation of TRPV1 reduces vascular lipid accumulation. Cardiovasc Res. 2011;92(3):504-513.
20. Minke B, Wu C, Pak WL. Induction of photoreceptor voltage noise. Nature. 1975;258:84-87.
21. Moller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, et al. Induction of TRPC6 channel in kidney disease. J Am Soc Nephrol. 2007;18(1):29-36.
22. Montell C, Birnbaumer L, Flockerzi V, Bindels RJ, Bruford EA, Caterina MJ, et al. A unified nomenclature for TRP channels. Mol Cell. 2002;9(2):229-231.
23. Naert R, Lopez-Requena A, Talavera K. TRPA1 in immune cells. Int J Mol Sci. 2021;22:11460.
24. Rahaman SO, Grove LM, Paruchuri S, Southern BD, Abraham S, Niese KA, et al. TRPV4 mediates pulmonary fibrosis. J Clin Invest. 2014;124(12):52255238.
25. Ranjan R, Das P, Batabyal S, Minj AP. TRPV6 expression in rabbit gut. World Rabbit Sci. 2020;28:187-197.
26. Toth BI, Olah A, Szollosi AG, Biro T. TRP channels in the skin. Br J Pharmacol. 2024;171:2568-2581.
27. Vanoevelen J, Janssens A, Huitema LFA, Hammond CL, Metz JR, Flik G, et al. TRPV5/6 and bone formation. FASEB J. 2011;25:3197-3207.
28. Vergnolle N. TRPV4 in inflammatory bowel disease. Biochem Pharmacol. 2014;89:157-161.
29. Vincent F, Duncton MA. TRPV4 agonists and antagonists. Curr Top Med Chem. 2011;11:2216-2226.
30. Wu LJ, Sweet TB, Clapham DE. Progress in mammalian TRP ion channels. Pharmacol Rev. 2010;62:381-404.
31. Yoneshiro T, Saito M. TRP-activated brown fat thermogenesis. Curr Opin Clin Nutr Metab Care. 2013;16:625-631.
32. Zeng X, Sikka SC, Huang L, Sun C, Xu C, Jia D, et al. TRPM2 in prostate cancer. Prostate Cancer Prostatic Dis. 2010;13(2):195-201.
33. Zhang HY, Chu JF, Li P, Li N, Lv ZH. TRPV1 in overactive bladder. J Biol Regul Homeost Agents. 2015;29(4):875-879.
34. Zhang M, Ma Y, Ye X, Zhang N, Pan L, Wang B. TRP ion channel family. Signal Transduct Target Ther. 2023;8:261-298.
35. Zsombok A, Derbenev AV. TRP channels in diabetes and obesity. Pharmaceuticals (Basel). 2016;9:50.
36. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, et al. Vanilloid receptors and vasodilation. Nature. 1999;400:452-457.