Significant advancements have been made in comprehending the mechanisms of pain perception since the initial discovery of the first TRP (transient receptor potential) sensory channel, known as the hot pepper receptor TRPV1, over two decades ago. Since then, other TRP channels with a role in pain have been discovered, yet our insight into this issue is still insufficient, as evidenced by the so far unsuccessful attempts to develop next-generation analgesics. The tempting concept of targeting TRP channels at the site where chemical or physical stimuli from the environment are directly converted into sensory neuronal activity is greatly complicated by their polymodality, i.e., the channels respond to and integrate a variety of stimuli of diverse origins.

In our lab, we focus on a subgroup of the TRP family that is directly activated by changes in ambient temperature, known as thermoTRPs. Recently we have directed our attention to TRPC5, whose inhibition in animal models leads to pain relief and which responds to noxious cold. On a single-channel level, we showed that the open probability of this channel increases robustly between 16 °C and 11 °C and reaches the saturation below 5 °C. Thermodynamic analysis revealed significant changes in enthalpy and entropy suggesting that substantial conformational changes accompany cold-induced gating.

Moreover, we explored the effects of duloxetine on TRPC5. This compound is the only drug that demonstrates efficacy for severe cold–induced pain states associated with diabetic and chemotherapy-induced neuropathy and its analgesic effect has been previously attributed to the inhibition of voltage-gated sodium channels. The combination of electrophysiological measurements, point mutagenesis, molecular docking and molecular dynamics simulations enabled us to show that duloxetine inhibits TRPC5 in a concentration-dependent manner with a potency within the physiological range. Thus, TRPC5 may contribute to the efficacy of duloxetine in cold-related pain.

Biography:

Lucie Zímová is a research fellow in the Laboratory of Cellular Neurophysiology at the Institute of Physiology (IPHYS) of the Czech Academy of Sciences in Prague. She completed her Ph.D. in biophysics at Faculty of Mathematics and Physics, Charles University in Prague. Her research is focused on elucidating the molecular mechanisms of thermosensitive transient receptor potential (TRP) ion channels activation.