TRPM2 in ischemic stroke: Structure, molecular mechanisms, and drug intervention

Abstract

Ischemic stroke has a high lethality rate worldwide, and novel treatments are limited. Calcium overload is considered to be one of the mechanisms of cerebral ischemia. Transient receptor potential melastatin 2 (TRPM2) is a reactive oxygen species (ROS)-sensitive calcium channel. Cerebral ischemia-induced TRPM2 activation triggers abnormal intracellular Ca²⁺ accumulation and cell death, which in turn causes irreversible brain damage. Thus, TRPM2 has emerged as a new therapeutic target for ischemic stroke. This review provides data on the expression, structure, and function of TRPM2 and illustrates its cellular and molecular mechanisms in ischemic stroke. Natural and synthetic TRPM2 inhibitors (both specific and nonspecific) are also summarized. The three-dimensional protein structure of TRPM2 has been identified, and we speculate that molecular simulation techniques will be essential for developing new drugs that block TRPM2 channels. These insights about TRPM2 may be the key to find potent therapeutic approaches for the treatment of ischemic stroke.

Keywords: TRPM2 blockers; TRPM2 channel; ischemic stroke; pathogenesis; virtual screening.

Figure 1.

TRPM2 consists of four subunits and has six transmembrane domains with a reentry loop between the fifth and sixth helices. The N termini and C termini are located in the intracellular loops. The intracellular N-terminus includes four highly conserved common regions and an IQ motif that binds CaM and Ca²⁺. The intracellular C-terminus contains a TRP box (TRP), a coiled-coil domain (CCD), and the nucleoside diphosphate-linked moiety X-type homology motif (NUDT9-H)

Figure 2.

Various stimuli can lead to TRPM2 activation. The elevation of ROS and H₂O₂ activate TRPM2 through production of intracellular ADPR. Extracellular factors including TNF-α and β-AP contribute to activation of TRPM2. Structural analogs of ADPR including NAADP, cADPR, OAADPR, and 2′-deoxy-ADPR activate TRPM2. Elevated Ca²⁺ and NAD⁺ can also participate in activation of TRPM2

Figure 3.

Mechanisms of neuronal TRPM2 in ischemic stroke. TRPM2 modulates NMDAR-dependent survival and death signal pathways. TRPM2 participate in PKC/NOX‐mediated ROS generation, Zn²⁺ accumulation and subsequent a vicious positive feedback signaling mechanism for delayed cell death. TRPM2 involves in NLRP3 inflammasome activation and secretion of CXCL2 and caspase-1

Figure 4.

Involvement of non-neuronal TRPM2 in immune responses. TRPM2 signaling control microglia cells and astrocytes function and responses through production of cytokines and chemotaxis. TRPM2 contributes to brain injury through activating peripheral immune cells including macrophages, neutrophils, and monocytes

Figure 5.

The role of TRPM2 in blood–brain barrier damage. TRPM2 is involved in endothelial cell damage and microvascular pericyte injury