Online Journal of Neurology and Brain Disorders DOI: 10.32474/OJNBD.2020.04.000192 ISSN: 2637-6628 Review Article Therapeutic Potential of TRPM Modulator Nitin Rawat, Hemprabha Tainguriya and Anil Kumar* Pharmacology Department, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies (UGC-CAS), Panjab University, India *Corresponding author: Anil Kumar, Professor of Pharmacology, Former Dean, Faculty of Pharmaceutical Sciences, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies (UGC-CAS), Panjab University, Chandigarh, India Received: September 24, 2020 Published: October 06, 2020 Abstract Transient Receptor Potential of the family Melastatin (TRPM) is a group of nonselective cation channel, engaged in various daily skin. Soon after TRPM1 was discovered, another family member was discovered, that includes TRPM2 (channel sensitive to oxidative stressactivities present of the in body. microglial The family’s cells), TRPM3first member (channel (TRPM1) activating was renalcloned homeostasis in 1998 capable that is of activated supressing by thesphingosine), tumour in TRPM4/5melanocytes (Ca of+2 activated sister channel involved in conduction of monovalent cation), TRPM6/7 (chanzymes related to Mg+2 homeostasis), TRPM8 (thermosensitive Ca+2 permeable channel). This review will summarize activation of key structural features mechanism and therapeutic potential of drug modulating TRPM channels. Keywords: Transient Receptor Potential (TRP) Channels; TRPM Modulators; Neurodegenerative Diseases; Cancer Introduction channels that are grouped according to amino acid sequence Transient Receptor Potential (TRP) channels are group of homology into six subfamilies. Canonical TRPs (TRPCs), Vanilloid membrane proteins that play a key role in managing variety of TRPs (TRPVs), Melastatin TRPs (TRPMs), Mucolipins (TRPMLs), physiological function ranging from controlling of second messenger Polycystins (TRPPs), Ankyrin transmembrane protein 1 (TRPA1) (Ca+2) availability and nerve conduction to sensing extracellular pH, osmolar balance of and environmental temperature(TRPV1–4, localization and activation/inhibition by different endogenous and TRPA1, and TRPM8) [1]. First TRP was brought into light after [2]. These subfamilies of TRPs are further classified based on their exogenous modulator. TRPM subfamily is one of the indispensable Cosens and Manning work in 1969, on photo transduction in group of ion-channel that is ubiquitously expressed and intricately Drosophila melanogaster) that exhibited involved in pathophysiology of various neurological disorder. In blindness under intense bright light, because it induces mutation mutant species of fruit fly ( this review, we focus on the complicity TRPM in various diseases in the trp gene of Drosophila, during the cloning of trp gene (Alzheimer’s, Parkinson’s cerebral ischemia neuropathic pain etc.) and underlying mechanism of its modulation for the treatment of 2010). Mammalian TRP subfamily contains 28 cation permeable first member of drosophila came into existence (Baruch Minke, these diseases (Figure 1). Copyright © All rights are reserved by Anil Kumar. 369 On J Neur & Br Disord Volume 4 - Issue 4 Copyrights @ Anil Kumar, et al. Figure 1: Subfamilies of TRP. TRPM Channel and its Structural Features like pregnenolone sulphate, that reveals its steroidal essence [3]. TRPM subfamily of ion channels has eight members, TRPM4/5 are monovalent non- selective cation channels that subdivided into four classes on the basis of their structural are activated by Ca2+. They have similarity (about 50% identical) similarity: TRPM1/3, TRPM6/7, TRPM4/5, and TRPM2/8. TRPM in their sequence homology and share common properties such protein consists of six transmembrane units, a pore between as channel regulation, ion selectivity, voltage-dependency. TRPM4 5 and 6 units and two intracellular regulatory domains (C and N-terminal contains a nucleotide binding domain (NBD) with ATP N-terminal). C-terminal comprised of 1000-2000 AA that include binding and channel inhibiting operations [4]. TRPM6/7 is a bi TRP box sequence and coiled-coil domain responsible for channel functional protein capable of penetrating ion (Mg2+, Zn2+ and Ca2+) tetramerization. The N-terminal consisting of 300-400 AA, has . At their C- terminal kinase protein domain that helps them to act various binding sites in different channel. The TRPM family has as chanzyme. TRPM7 ubiquitously expressed, primarily involved varying degree of permeability of Ca+2 and Mg+2 permeability from in the conduction of Mg2+ and Zn2+. It is needed for the embryonic impermeable (TRPM4/5) to extremely permeable (TRPM6/7), mouse development [5]. three members(TRPM2/6/7) are chanzymes (includes enzyme in Unlike TRPM6/7, TRPM2 is also a bi-functional cation channel intracellular C-domain, TRPM2 has nudix hydrolases (NUDT9-H) which is permeable to Ca2+, Na+ and K+. C-terminal of TRPM2 is and TRPM6/7 have kinase proteins) [1]. mapped with enzyme nudix hydrolases (NUDT9-H) which binds to TRPM1/3 are cation channels that are non-selective calcium ADPR and activates TRPM2. High Intracellular Ca2+ concentration permeable. In human, TRPM subfamily member i.e. TRPM1 which can activate the TRPM independently or in combination with ADPR is cloned from benign melanomasgeneis based on face, skin, eye by binding to the N- terminus with a calmodulin-binding motif [6]. and pigment cell chromosome 15, which contains 5.4kb mRNA TRPM8 is a nonselective, temperature sensitive Ca+2 permeable transcript, encodes to 1603AA. TRPM3’s C-terminal includes TRP cation channel, situated in dorsal root ganglion (DRG) of sensory box whereas N-terminal contains two Calmodulin binding sites. neurons and trigeminal neurons. It is predominantly cloned from Like TRPM1, TRPM3 has 6 mRNA transcript forms cloned from prostate cancer cell. Phosphoinositide binds with C- terminal and human kidney. TRPM3 is found in human’s brain and kidney and is TRP box sequences, modulates the activity of TRPM8. Coiled coil involved in renal osmo-homeostasis. TRPM3 is triggered by steroids and activation by temperature [7] (Figure 2) (Table 1). C-terminal domain is responsible for channel assembly, trafficking, Citation: Nitin Rawat, Hemprabha Tainguriya, Anil Kumar. Therapeutic Potential of TRPM Modulator. On J Neur & Br Disord 4(4)- 2020. OJNBD.MS.ID.000192. DOI: 10.32474/OJNBD.2020.04.000192. 370 On J Neur & Br Disord Volume 4 - Issue 4 Copyrights @ Anil Kumar, et al. Figure 2. Table 1: Functional role of TRPM modulators. TRPMs and their location Physiological Function Disease Modulators bipolar cell depolarisation; prognostic TRPM1 Stationary congenital Stimulators: Pregnenolone sulphate marker of tumour suppression for nocturnal blindness. 2+ Brain, melanocytes, eye, skin melanoma metastasis. Inhibitors: Zn Stimulators: 2-P-ADPR, 3-P-ADPR, 2 F-ADPR, AMPCPR, ADPR,Ca cADPR,2+ 2′-deoxy-ADPR, TRPM2 Sensation of core body temperature; Bipolar disorder, Cerebral Inhibitors: Clotrimazole, econazole Macrophages, brain, Oxidative sensation; Insulin secretion; ischaemia, Alzheimer`s Immune reaction. disease, Neuropathic pain anthranilic acid, 2-APB, scalardial, 3-MFA, marrow flufenamic acid, N-(p- amylcinnamoyl) pancreatic β cells, bone 8-Br-cADPR, 8-Br-ADPR, 8-Ph- ADPR, 8-Ph- 2-deoxy-ADPR, 8-(3-acetylphenyl)-ADPR, 8-thiophenyl-ADPR, and More TRPM3 Stimulators: Sphingolipids, pregnenolone Neurotransmitter release regulator, iris sulfate (PS), and nifedipine, CIM0216 Dorsal root ganglia, Kidney constriction, renal osmo-homeostasis, Cataract, glaucoma, Visual extracellular osmolarity, swelling, heat cardiomyocytes, pancreatic Glucose homeostasis, sensitive to epilepsy; Retinal disorder. (40°C). beta-cells, Nociceptive Primary neurons Inhibitors: primidone temperature and inflammatory pain. Ca+2 dependent Dendritic cell activation TRPM4 2+ and T-lymphocyte Secretion of Insulin Brugada syndrome; Stimulators: Ca Pancreas, heart, prostate, Prevention of heart conduction disorders Cardiac conduction fault. renal tubule, and liver Inhibitors: ATP, ADP, AMP, 9-phenanthrol. Regulation of smooth muscle contraction. 2+ 2 TRPM5 Stimulators: Ca , PIP , steviol glycosides, Modulation of insulin secretion and rutamarin. Taste bud, beta-cells sensory transduction in taste Beckwith-Wiedemann of pancreas; Tuft cells; syndrome Inhibitors: TPPO cells. Chemosensory Solitary cells. (Triphenylphosphorus oxide) Renal Magnesium homeostasis and TRPM6 intestine. Secondary hypocalcaemia Stimulators: Mg2+ Intestine, brain, pituitary, Has an atypical kinase domain, letting (HSH) autosomal recessive and distal convoluted tubule Inhibitors: ruthenium red them to work as “Chanzymes,” capable of hypomagnesemia (DCT) of the kidney phosphorylating and Channel activation. Citation: Nitin Rawat, Hemprabha Tainguriya, Anil Kumar. Therapeutic Potential of TRPM Modulator. On J Neur & Br Disord 4(4)- 2020. OJNBD.MS.ID.000192. DOI: 10.32474/OJNBD.2020.04.000192. 371 On J Neur & Br Disord Volume 4 - Issue 4 Copyrights @ Anil Kumar, et al. Mg2+- and Ca2+-permeable cation channel Stimulators: Mg2+-ATP, breakdown of PIP2, with activity on protein kinase. rise in cAMP concentrations TRPM7 Has an atypical kinase domain, letting Neurodegenerative Inhibitors: Mg2+, spermine, 2-APB(2- Ubiquitously present them to work as “chanzymes,” capable disorders Aminoethyl diphenylborinate), of phosphorylating and activating the MnTBAP(manganese (III) tetrakis channel. (4-benzoic acid) porphyrin) TRPM8 Stimulators: cool temperature (<28°C)