TRPM2: a multifunctional ion channel for calcium signalling

Abstract

The transient potential receptor melastatin-2 (TRPM2) channel has emerged as an important Ca 2+ signalling mechanism in a variety of cells, contributing to cellular functions that include cytokine production, insulin release, cell motility and cell death. Its ability to respond to reactive oxygen species has made TRPM2 a potential therapeutic target for chronic inflammation, neurodegenerative diseases, and oxidative stress-related pathologies. TRPM2 is a non-selective, calcium (Ca 2+ )-permeable cation channel of the melastatin-related transient receptor potential (TRPM) ion channel subfamily. It is activated by intracellular adenosine diphosphate ribose (ADPR) through a diphosphoribose hydrolase domain in its C-terminus and regulated through a variety of factors, including synergistic facilitation by [Ca 2+ ] i , cyclic ADPR, H 2 O 2 , NAADP, and negative feedback regulation by AMP and permeating protons (pH). In addition to its role mediating Ca 2+ influx into the cells, TRPM2 can also function as a lysosomal Ca 2+ release channel, contributing to cell death. The physiological and pathophysiological context of ROS-mediated events makes TRPM2 a promising target for the development of therapeutic tools of inflammatory and degenerative diseases.

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

“…A potential link between NAD depletion and T1D was demonstrated by the findings that knockout of PARP in mice prevents streptozotocin (STZ)-induced β-cell death and hyperglycaemia [5,7]. Subsequent studies however have shown that ADP-ribose, the by-product of NAD metabolism, is a potent activator of the transient receptor potential (melastatin) 2 (TRPM2) channel [8] and inhibition of TRPM2 channels prevents apoptosis [9][10][11][12]. These later results raised the possibility that TRPM2 (ADPribose)-mediated β-cell apoptosis could also contribute to T1D, but its role relative to energy depletion has not been investigated.…”

“…Although H 2 O 2 can directly activate the channel, activation is largely mediated by ADP-ribose [8,[10][11][12]. The channels are also directly activated through the oxidation of a methionine located in the cytoplasmic N-terminal domain [13].…”

“…The TRPM2 channel is proposed to play a dual role in β-cell physiology with modest TRPM2-mediated Ca 2 + elevation being implicated in glucose-stimulated insulin secretion [15,16], although the in vivo evidence in TRPM2-knockout mice is somewhat controversial [15,17]. However, strong activation of the channel causes excessive Ca 2 + elevation resulting in β-cell death [9,11,12,14,18]. Interestingly, a previous study demonstrated that TRPM2 channels can be permeate by Zn 2 + ions [19].…”

Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues

“…The characters of these two inhibitors probably attribute to the nature of ADPR analogues. It is well known that ADPR gates TRPM2 through binding to the cytosolic C‐terminal NUDT9‐H domain which is a unique structure domain among TRP channels 5. The two inhibitors 7i and 8a likely compete with ADPR for binding to the NUDT9‐H domain, serving as intracellular inhibitors.…”

“…TRPM2, a subtype of TRP‐melastatin subfamily (TRPM), is a multifunctional Ca 2+ permeable and nonselective cation channel 4. It functions as an important Ca 2+ signalling regulator in a variety of cells, contributing to cellular functions including cytokine production, insulin release, cell motility, oxidative stress and cell death 5. TRPM2 is activated by reactive oxygen species (ROS) such as hydrogen peroxide and is considered as a chanzyme containing a unique C‐terminal Nudix hydrolase domain, that is homologous to the ADPR pyrophosphatase nudix hydrolase 9 (NUDT9) 6, 7, 8.…”