Contribution of KCNQ and TREK Channels to the Resting Membrane Potential in Sympathetic Neurons at Physiological Temperature

Abstract

The ionic mechanisms controlling the resting membrane potential (RMP) in superior cervical ganglion (SCG) neurons have been widely studied and the M-current (IM, KCNQ) is one of the key players. Recently, with the discovery of the presence of functional TREK-2 (TWIK-related K+ channel 2) channels in SCG neurons, another potential main contributor for setting the value of the resting membrane potential has appeared. In the present work, we quantified the contribution of TREK-2 channels to the resting membrane potential at physiological temperature and studied its role in excitability using patch-clamp techniques. In the process we have discovered that TREK-2 channels are sensitive to the classic M-current blockers linopirdine and XE991 (IC50 = 0.310 ± 0.06 µM and 0.044 ± 0.013 µM, respectively). An increase from room temperature (23 °C) to physiological temperature (37 °C) enhanced both IM and TREK-2 currents. Likewise, inhibition of IM by tetraethylammonium (TEA) and TREK-2 current by XE991 depolarized the RMP at room and physiological temperatures. Temperature rise also enhanced adaptation in SCG neurons which was reduced due to TREK-2 and IM inhibition by XE991 application. In summary, TREK-2 and M currents contribute to the resting membrane potential and excitability at room and physiological temperature in the primary culture of mouse SCG neurons.

Are TREK Channels Temperature Sensors?

“…Consistently, TREK2 knockdown (siRNA C) has been shown to depolarize small rat DRG neurons by about 10 mV, suggesting a major role of TREK2 channels on the resting membrane potential (RMP) at 37 • C (Acosta et al, 2014). However, at 24 • C, TREK channels showed a very low activity and other K2P channels (TRESK) became more relevant at the resting level Rivas-Ramírez et al, 2020a). The reason why different authors disagree on which of the two channels, TREK1 or TREK2 is more abundant in DRG neurons is unknown.…”

“…Surprisingly, cultured DRG neurons from TREK1-KO mice were reported to show the same RMPs than the neurons obtained from WT animals, unfortunately this experiment was carried out at room temperature and not repeated at more physiological temperatures (Alloui et al, 2006). It is worth noting that the contribution of TREK channels to the RMP maintenance cannot be fully appreciated at room temperature since they have practically no activity in these conditions (Rivas-Ramírez et al, 2020a).…”

“…Similarly, c-Fos activity is increased in Grueneberg ganglion neurons when mice pups are exposed to 22 • C for 2 h and this effect is weaker in TREK1-KO mice but independent of TRPs (Stebe et al, 2014). Although the basis of this behavior is not totally understood, the presence of TREK channels may contribute to it (Reid and Flonta, 2001;Viana et al, 2002;Munns et al, 2007;Cadaveira-Mosquera et al, 2011, 2012Vetter et al, 2013;MacDonald et al, 2020;Rivas-Ramírez et al, 2015, 2020a. Consistently, mice lacking both TREK1 and TRAAK channels (but not those lacking only one of them) showed a percentage of small diameter DRG neurons responding to cold higher (54%) that their wild counterparts (Noël et al, 2009).…”

Neurodegenerative Disease Diagnosis via Ion‐Level Detection in the Brain

“…K + , H + , Na + , and Cl − can traverse across the corresponding ion channels on cytomembrane to regulate the cell excitability and the release of neurotransmitters via adjusting the resting membrane potential and action potential. [ 6 ] For example, ATP‐sensitive K + channels are involved in controlling resting membrane potential due to the K + efflux, [ 7 ] while selective permeation of K + via voltage‐dependent K + (Kv) channels can efficiently modulate the shape and frequency of action potential, and repolarization in the neurons. [ 8 ] In addition, H + ‐associated proton pumps are closely related to the mitochondrial membrane potential, which is essential for the energy storage and the generation of ATP.…”

Activity of TREK-2-like Channels in the Pyramidal Neurons of Rat Medial Prefrontal Cortex Depends on Cytoplasmic Calcium

“…Mice in which the TREK-1 channel has been deleted have an increased vulnerability to both epileptic seizure and cerebral ischemia [ 14 ] and are resistant to depression [ 6 , 15 ]. TREK channels show relatively low basal activity that is increased by physical and chemical stimuli, including temperature, membrane stretch, pH, unsaturated fatty acids [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], and PI(4,5)P2 [ 26 ]. The C-terminus of TREK is crucial for the sensitivity to intracellular pH and membrane stretching [ 27 , 28 ] as well as PI(4,5)P2, the phosphatidylinositol present in the inner leaflet of the plasma membrane.…”