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Review
. 2018 May;39(5):722-732.
doi: 10.1038/aps.2018.31. Epub 2018 Apr 19.

TRPM2: a candidate therapeutic target for treating neurological diseases

Jillian Corinne Belrose  1 , Michael Frederick Jackson  2   3
Affiliations
Review

TRPM2: a candidate therapeutic target for treating neurological diseases

Jillian Corinne Belrose et al. Acta Pharmacol Sin. 2018 May.

Abstract

Transient receptor potential melastatin 2 (TRPM2) is a calcium (Ca2+)-permeable non-selective cation channel belonging to the TRP ion channel family. Oxidative stress-induced TRPM2 activation provokes aberrant intracellular Ca2+ accumulation and cell death in a variety of cell types, including neurons. Aberrant TRPM2 function has been implicated in several neurological disorders including ischemia/stroke, Alzheimer's disease, neuropathic pain, Parkinson's disease and bipolar disorder. In addition to research identifying a role for TRPM2 in disease, progress has been made in the identification of physiological functions of TRPM2 in the brain, including recent evidence that TRPM2 is necessary for the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression, an important form of synaptic plasticity at glutamate synapses. Here, we summarize recent evidence on the role of TRPM2 in the central nervous system (CNS) in health and disease and discuss the potential therapeutic implications of targeting TRPM2. Collectively, these studies suggest that TRPM2 represents a prospective novel therapeutic target for neurological disorders.

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Figures

Figure 1
Figure 1
TRPM2 Isoforms. Schematic representation of full-length TRPM2 and TRPM2 isoforms, demonstrating the approximate locations of domains and deletions. The N-terminus of TRPM2 contains the TRPM homology domain and the IQ-like motif. This is followed by six transmembrane domains, with a pore-forming re-entry loop between domains 5 and 6. The C-terminus contains the coiled-coiled (CC) motif and the NUDT9-H motif. TRPM2 isoforms include TRPM2-ΔN (deletion of amino acids (aa) 538-557); TRPM2-ΔC (deletion of aa 1292-1325); TRPM2-ΔNΔC (deletion of aa538-557 and aa1292-1325); striatum short form TRPM2 (SSF-TRPM2, deletion of aa1-214); TRPM2-S, a variant that is truncated after the second transmembrane domain, producing an 845-residue splice variant; and TRPM2-TE, a splice variant identified with computational analysis demonstrating up-regulated expression in melanoma and other tumor types,,,,,.
Figure 2
Figure 2
TRPM2 Structure. TRPM2 is comprised of intracellular amino and carboxy-terminal regions and six transmembrane segments with a re-entry loop that forms a pore between segments 5 and 6. The amino terminus contains the TRPM2 homology domain, which is largely conserved across all TRPM family members. The amino terminus also contains a Ca2+-calmodulin (CaM) binding motif that participates in channel activation. The carboxy terminus contains a highly conserved TRP box (TRP), a coiled-coiled region (CCR) that may participate in tetrameric assembly, and the nucleoside diphosphate-linked moiety X-type homology motif (NUDT9-H), which binds adenosine diphosphate ribose (ADPR), the intracellular agonist for TRPM2.
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