PhD Scientific Days 2026

Poster Session 1.A - Molecular Medicine

Molecular Characterization of a TRPM2 Cation Channel Variant Associated with Bipolar Disorder

Name of the presenter

Tóth, Ádám

Institute/workplace of the presenter

Department of Biochemistry, Semmelweis University, Budapest, Hungary

Authors

Tóth Ádám¹, Csanády László¹, Bartók Ádám¹
1: Department of Biochemistry, Semmelweis University, Budapest, Hungary

Text of the abstract

TRPM2 is a Ca2+-permeable cation channel that has been recognized as a cellular sensor of oxidative stress. It plays a role in immune cell activation, apoptosis, and oxidative stress response. Recent studies have revealed that TRPM2 also functions as a highly sensitive thermosensor, and thermoregulatory impairments have been observed in gene knockout mice. Moreover, genetic association studies have identified the common TRPM2-D543E variant (MAF = 0.205 globally), which has been linked to bipolar disorder. This variation results in an exchange of an Asp to Glu at position 543.
The aim of this study was to elucidate the functional consequences of D543E substitution in TRPM2 channel activity. To this end, the variant was transiently expressed in HEK cells. Functional characterization was performed in a cell-free system using the inside-out patch-clamp configuration, enabling precise analysis of channel gating properties, ligand sensitivity (Ca²⁺, ADPR), and temperature dependence.
Our results show that the apparent Ca²⁺ affinity of the D543E variant is increased at all tested temperatures (15 °C, 25 °C, and 37 °C), whereas the apparent affinity for ADPR remains largely unchanged. Analysis of channel open probabilities across different temperatures revealed a reduced temperature sensitivity. Due to its increased Ca²⁺ affinity, the variant sustains a higher Ca²⁺ current under physiological conditions (37 °C, 100 nM Ca²⁺, 2 µM ADPR) compared to the wild-type.
In summary, functional analyses revealed differences between the TRPM2-D543E and the wild-type channel. The increased Ca²⁺ sensitivity of the variant leads to enhanced Ca²⁺ influx, which may contribute to elevated neuronal excitability. Furthermore, temperature sensitivity of TRPM2 appears to be finely tuned to the physiological range. As the variant exhibits enhanced activity at the molecular level, this alteration probably shifts thermosensation to non-physiological range, potentially leading to impaired physiological thermoregulation. However, further studies are required to elucidate the role of this variant in the pathogenesis of bipolar disorder.
This work was supported by the Hungarian Centre of Excellence for Molecular Medicine (H-CEMM), National Research, Development and Innovation Office ADVANCED (149640) grant, HUN-REN Office for Supported Research Groups, SE 250+ Excellence PhD Scholarship.