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Advanced Neurology TRPM2 in neurological disorders

Figure 2. Interrelated molecular mechanisms by which TRPM2 activation induces neurological injury or disease. Activation of TRPM2 in the cell
membrane or increased levels of TRPM2, both in response to oxidative stress, cause the excessive influx of ions such as Ca or Zn into the cell. The
2+
2+
resultant Ca -ionic imbalance induces a variety of intracellular processes, including augmented ROS production, which facilitates the production of
2+
ADPR, exacerbating TRPM2-mediated Ca influx. This leads to the activation of key signaling molecules which ultimately induce apoptosis, activate
2+
glial cells and neuroinflammation, cause mitochondrial dysfunction, and reduce antioxidant activity. These pathological mechanisms have been highly
implicated in the etiology of neurological disorders including PD, AD, ischemic stroke, TBI, BP, and depression.
upregulated in the brains of socially isolated mouse injury and functional deficits. Finally, TRPM2 at the mRNA
models of depression [136,137] . Interestingly, the serotonin and protein levels is upregulated in the hippocampus of
and norepinephrine reuptake inhibitor, duloxetine, reduces CUS-induced depressed mice, which is consistent with
Ca flux and inhibits oxidative stress and apoptosis. the upregulation of Trpm2 mRNA in the post-mortem
2+
This indicates an important role for the Ca -permeable hippocampal tissue of MDD patients compared with
2+
TRPM2 channel in depression, particularly given its role healthy controls [100] . Therefore, TRPM2 is highly implicated
in neuroinflammation and mediating neuronal death. in the pathology of depression at both the cellular and
Duloxetine increases antioxidant glutathione levels and functional levels, warranting further investigation into its
reduces H O -induced TRPM2 calcium transients, which therapeutic potential for the treatment of MDD.
2
2
is associated with a reduction in lipid peroxidation and
ROS levels [101] . Furthermore, in a CUS model of depression, Table 1 presents a summary of the studies discussed in
CUS TRPM2 mice had reduced lipid peroxidation and Section 4.
-/-
PARP levels in the hippocampus compared with CUS 5. Summary and conclusions
TRPM2 mice [100] . TRPM2 mice were also protected
-/-
+/+
against CUS-induced depressive-related behavioral This review discusses the mechanisms behind the
deficits compared with CUS TRPM2 mice. Cultured contribution of TRPM2 to neurodegenerative diseases,
+/+
2+
TRPM2 hippocampal neurons also have reduced H O - injuries, and psychiatric disorders. As a Ca -permeable
-/-
2
2
induced ROS accumulation and cyclin-dependent kinase 5 ion channel that is also responsive to other ions such as zinc,
(Cdk5) hyperactivation. Aberrant hyperactivation of Cdk5 its activation in response to ROS and tissue injury alters
is typically observed in depression and results in antioxidant intracellular ion homeostasis. This activates pathways,
enzyme inhibition and ROS accumulation [100] . This study leading to apoptosis, release of inflammatory mediators,
also indicates that in depression, TRPM2 signaling is and mitochondrial production of ROS (Figure 2).
associated with ROS-induced Cdk5 activity, which induces Consequently, although the various neurological diseases
a feed-forward signaling response, exacerbating oxidative discussed here are different (i.e., PD vs. AD), some of the
stress within the cell and ultimately leading to neuronal underlying mechanisms of cell death or dysfunction are
Volume 1 Issue 1 (2022) 11 https://doi.org/10.36922/an.v1i1.3