TRPM Assays

Background of TRPM

The mammalian TRPM subfamily consists of eight members, which share ~20% amino acid identities to TRPC channels over the C-terminal five transmembrane domains. Based on sequence homology, TRPMs fall into three subgroups: TRPM1-3, TRPM4-5, and TRPM6-7. Some of the TRPMs are located on intracellular membranes. TRPM proteins have a TRP domain C-terminal to the transmembrane segments. The total amino acid lengths (~1000–2000) and sequences of the C-terminal regions of these proteins vary considerably. Based on similarities in amino acid sequences, these proteins fall into subsets consisting of TRPM1/3, TRPM4/5, and TRPM6/7. TRPM2 and TRPM8 are not placed in any subset, although they are most closely related to each other. TRPM2 and TRPM6/7 are unusual in that they are chanzymes, with C-terminal enzyme domains.

Fig. 1 Structure overview of TRPM2, TRPM4, and TRPM8. Fig. 1. Structure overview of TRPM2, TRPM4, and TRPM8. (Huang, 2020)

Subtypes, Functions, and Mechanisms of TRPM

Gene	Functions	Diseases	Activator	Blocker
TRPM1	Depolarization of the bipolar cell; suppresses melanoma metastasis.	Congenital stationary night blindness.	Pregnenolone sulphate	Zn²⁺
TRPM2	Core body temperature sensation; Oxidative sensation; Insulin secretion; Immune response.	Bipolar disorder; Ischaemia-reperfusion	ADPR cADPR 2'-deoxy-ADPR 2'-P-ADPR 3'-P-ADPR 2-F-ADPR AMPCPR	Conazole Clotrimazole flufenamic acid Scalardial 3-MFA 8-Br-cADPR 8-Br-ADPR
TRPM3	Glucose homeostasis; Heat sensation and inflammatory pain.	Visual epilepsy, retinal dystrophy.	Pregnenolone sulphate CIM0216	Primidone
TRPM4	Regulation of calcium oscillations after T cell activation, prevention of cardiac conduction disorders. Regulating smooth muscle contraction.	Brugada syndrome, Cardiac conduction defect	Ca²⁺	ATP ADP AMP DVT 9-Phenanthrol
TRPM5	Modulation of insulin secretion and sensory transduction in taste cells.	Beckwith-Wiedemann syndrome	Ca²⁺ PIP2 Steviol glycosides Rutamarin	TPPO
TRPM6	Magnesium uptake and homeostasis in kidney and intestine.	Hypomagnesemia.	Mg²⁺	Ruthenium red
TRPM7	Magnesium and Calcium homeostasis, cell viability.	Neuronal degenerative diseases.	Mg²⁺-ATP	Mg²⁺ Spermine 2-APB MnTBAP
TRPM8	Cold sensation.	Inflammatory/neuropathic pain; prostate cancer.	Menthol Icilin	WS-12 CPS-369

Published Data

Paper Title	Possible involvement of TRPM2 activation in 5-fluorouracil-induced myelosuppression in mice
Journal	Eur J Pharmacol
Published	2021
Abstract	5-Fluorouracil (5-FU) is one of the pyrimidine antimetabolite drugs and is widely used in the treatment of cancers such as colorectal cancer, esophageal cancer, pancreas cancer, and breast cancer. 5-FU exerts its antitumor activity through the inhibition of thymidylate synthase leading to cancer cell death, accompanied by the arrest of the cell cycle. The major adverse effect of 5-FU is myelosuppression due to cell cycle arrest, and myelosuppression is a dose-limiting factor for 5-FU-based chemotherapy. Transient receptor potential melastatin 2 (TRPM2) is a Ca²⁺-permeable channel that is activated by oxidative stress induced by ROS such as H₂O₂. The expression of TRPM2 has been observed in the brain, hematopoietic stem cells, pancreatic β-cells, lungs, and leucocytes. In various types of cells, the activation of TRPM2 channels induced by ROS has been known to mediate cell death through an intracellular Ca²⁺ overload. Therefore, TRPM2 activation leading to cell death may be involved in 5-FU-induced myelotoxicity. However, there is no report investigating TRPM2 activation in 5-FU-induced myelotoxicity leading to myelosuppression. In the present study, researchers first investigated the effect of 5-FU on TRPM2 activation and found that 5-FU enhances TRPM2 activation induced by H₂O₂ in TRPM2-expressed human embryonic kidney 293 (HEK) cells, hematopoietic stem cells (HSCs), and hematopoietic progenitor cells (HPCs). In addition, the reduction of colony number and leukocytes in blood by 5-FU administration was alleviated by Trpm2 deficiency. These results suggested that TRPM2 contributes to 5-FUinduced myelotoxicity leading to myelosuppression.
Result	Researchers found that 5-FU treatment enhanced H₂O₂-induced TRPM2 activation and TRPM2 involved in 5-FU-induced myelosuppression in mice. Myelosuppression is one of the most frequent adverse effects of 5-FU-based chemotherapy, and readily causes infection, febrile neutropenia, and so on. These results suggest that TRPM2 is a valuable therapeutic target for 5-FU-induced myelosuppression.

References

Huang, Y.; et al. A structural overview of the ion channels of the TRPM family. Cell Calcium. 2020, 85: 102111.
Ishibashi, M.; Possible involvement of TRPM2 activation in 5-fluorouracil-induced myelosuppression in mice. European Journal of Pharmacology. 2021, 891: 173671.

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