Investigation of the Coregulation of Leak Potassium and TRPM8 Currents in Cold Receptors

Investigation of the Coregulation of Leak Potassium and TRPM8 Currents in Cold Receptors

Cold receptors sense temperature and temperature change. Neurons containing TRPM8 channels are activated by temperature decreases. These channels are expressed on sensory neurons of the dorsal root ganglion (DRG) and trigeminal ganglion (TG) with the temperature threshold of approximately 28°C. Once activated, they produce a cold sensation. Since TRMP8 channels could also be activated by agonists such as menthol and volatile anaesthetics (VA), they can prompt a cooling sensation without actual cooling and produce shivering or other reactions in patients during surgery(Vanden Abeele et al., 2013). In general, VAs cause change in transitions between different patterns of activity to start spiking activity at higher temperature and proceed with sequence of bursting pattern change in a narrower range of temperature (Korogod et al., 2020). Importantly, TRPM8 channels are co-expressed with the potassium leak channel (TASK-3) (Morenilla-Palao et al., 2014). Once activated, TASK-3 receptors cause an overall hyperpolarization of these neurons. TASK-3 receptors can also be activated by VAs and decrease the excitability of cold afferent neurons(Zhou, C et. al., 2012). To investigate the role of coactivation of TRPM8 and TASK-3 current, we used a single compartment model describing the dynamics of the cold receptors (Olivares, et al., 2015, Korogod et al., 2020). For this study, we upgraded the model to include a leak potassium TASK-3 current. Both currents, TRPM8 and TASK-3, are altered by volatile anaesthetics, which is governed by specific biophysical parameters within this model. We investigate how TASK-3 current activated by VAs would affect the patterns of spiking activity like bursting with different number of spikes per burst and compare them to the effects of temperature on cold receptors with TRMP8 current as previously reported (Olivares, et al., 2015, Korogod et al., 2020). We found that activation of TASK-3 current generally reduces the excitability of the receptor cell, shifting the borders of patterns of activities in the space of TRPM8 and TASK-3 parameters and temperature. We also investigated trasient responses of the receptor to different chilling protocols. Our study will help to alleviate side effects of VA such as shivering during surgical procedures.