TRPM2

TRPM2 is the acronym for "Transient Receptor Potential Cation Channel, Subfamily M, Member 2". TRPM2 is a protein that in humans is encoded by the TRPM2 gene on chromosome 21q22.3. The protein encoded by this gene is a non-selective calcium permeable cation channel. It belongs to the transient receptor potential (TRP) ion channel superfamily. Its closest relative is the cold- and menthol-activated TRPM8 ion channel. TRPM2, although not cold-sensitive, is activated by heat.

The term "TRP channels" = transient receptor potential channels, covers a large family of cellular ion channels. To date, 28 Trp channel genes have been identified in mammals (Nilius B et al. 2011). TRP channels exert important functions in primary signaling pathways in both vertebrates and non-vertebrates by being responsible for the regulated influx of Ca2+ into a cell upon activation. TRP channels in humans play an important receptive role in the processing of different types of taste (sweet, bitter, umami), furthermore in the perception and processing of pain, heat, cold, pressure or light impulses. For example, some TRP channels in the body are thought to behave like microscopic thermosensors. Some TRP channels are activated by molecules found in everyday spices such as garlic (allicin), chili pepper (capsaicin), wasabi (allyl isothiocyanate). Other channels are activated by menthol, camphor, peppermint and cannabis. Some channels act as sensors for osmotic pressure, volume, stretch and vibration.

The physiological role of TRPM2 has not been extensively studied. What is known is that TRPM2 activates by producing ADP-ribose (ADPR) after oxidative stress. ADP-ribose is produced by the enzyme PARP in response to oxidative stress and increases the propensity of cells to undergo apoptosis (Malko P et al. 2020). It has been shown to be involved in insulin secretion (Togashi K et al 2006). In immune cells, it mediates parts of the responses to TNF-alpha. Furthermore, TRPM2 appears to play a role in the activation of the NLRP3 inflammasome, the dysregulation of which is strongly associated with a number of auto-inflammatory and metabolic diseases such as gout, obesity and diabetes (Zhong Z et al. 2013). Furthermore, TRPM2 appears to be a sensor for detecting heat in the non-harmful range of 33-38 °C (Tan CH et al. 2016 and 2018).

CNS: The TRPM2 gene is highly expressed in the brain and has been linked to bipolar affective disorder (manic depression) both by genetic linkage studies in families. In the brain, TRPM3 is involved in the toxicity of amyloid beta, a protein associated with Alzheimer's disease.

Tumor cells: Expression of TRPM2 in cells is associated with increased viability of a number of cell types following oxidative stress. Activation of TRPM2 leads to the expression of transcription factors and kinases important for cell proliferation and survival, including CREB, Nrf2, Pyk2, and others (Miller BA 2019).TRPM2 maintains tumor cell viability (Malko P et al 2020). TRPM2 channels are highly expressed in several tumor types such as breast, prostate, and pancreatic cancer, in melanoma, and neuroblastoma (Hirschler-Laszkiewicz I et al. 2018), and in myeloid leukemia. There is evidence that targeting TRPM2 may be a novel therapeutic approach in some tumor types (Miller BA 2019).

1. Hirschler-Laszkiewicz I et al. (2018) The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation. Am J Physiol Cell Physiol 315:C571-C586.
2. Malko P et al. (2020) TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions. Redox Biol 37:101755.
3. Miller BA (2019) TRPM2 in Cancer. Cell Calcium 80:8-17.
4. Nilius B et al (2011) The transient receptor potential family of ion channels. Genome Biol 12:218.
5. Tan CH et al (2016) The TRPM2 ion channel is required for sensitivity to warmth. Nature 536: 460-463.
6. Tan CH et al. (2018) TRPM2 and warmth sensation. Pflugers Arch 470:787-798.
7. Togashi K et al. (2006) TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion". The EMBO Journal 25: 1804-1815.
8. Yamamoto S et al (2008) TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nature Medicine 14: 738-747
9. Zhong Z et al (2013) TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nature Communications 4: 1611.