TREK-2 (K_2P10.1) and TRESK (K_2P18.1) are major background K⁺ channels in dorsal root ganglion neurons

Abstract

Dorsal root ganglion (DRG) neurons express mRNAs for many two-pore domain K(+) (K(2P)) channels that behave as background K(+) channels. To identify functional background K(+) channels in DRG neurons, we examined the properties of single-channel openings from cell-attached and inside-out patches from the cell bodies of DRG neurons. We found seven types of K(+) channels, with single-channel conductance ranging from 14 to 120 pS in 150 mM KCl bath solution. Four of these K(+) channels showed biophysical and pharmacological properties similar to TRESK (14 pS), TREK-1 (112 pS), TREK-2 (50 pS), and TRAAK (73 pS), which are members of the K(2P) channel family. The molecular identity of the three other K(+) channels could not be determined, as they showed low channel activity and were observed infrequently. Of the four K(2P) channels, the TRESK-like (14 pS) K(+) channel was most active at 24 degrees C. At 37 degrees C, the 50-pS (TREK-2 like) channel was the most active and contributed the most (69%) to the resting K(+) current, followed by the TRESK-like 14-pS (16%), TREK-1-like 112-pS (12%), and TRAAK-like 73-pS (3%) channels. In DRG neurons, mRNAs of all four K(2P) channels, as well as those of TASK-1 and TASK-3, were expressed, as judged by RT-PCR analysis. Our results show that TREKs and TRESK together contribute >95% of the background K(+) conductance of DRG neurons at 37 degrees C. As TREKs and TRESK are targets of modulation by receptor agonists, they are likely to play an active role in the regulation of excitability in DRG neurons.

Mixing and matching TREK/TRAAK subunits generate heterodimeric K 2P channels with unique properties

“…In an opposite manner, stimulation of the Gi-coupled adrenergic (α2AR), glutamate (mGluR2, mGluR4), γ-aminobutyrate (GABA B R) receptors activates TREK1 and TREK2 through adenylate cyclase inhibition, producing a decrease of cyclic adenosine monophosphate and PKA activity favoring channel dephosphorylation (3,8,38). Phosphorylation by PKC induces inhibition of TREK1 and/or TREK2 by Gq-coupled receptors through TSH releasing hormone receptor, orexin, acetylcholine (M3-R), and neurotensin (1,15,36). Other pathways contributing to Gq-mediated inhibition of TREK channels include mGluR1 activation through direct diacylglycerol and phosphatidic acid effects or through phosphatidylinositol 3,5-bisphosphate breakdown rather than activation of PKC (29).…”

“…Finally, inhibition of TREK1 by spadin (10), an endogenous peptide, or by the antidepressant fluoxetine (Prozac) (11), pinpoints it as a valuable target for the treatment of depression. TREK/TRAAK channels are broadly expressed in the nervous system (12)(13)(14)(15). TREK1 is more specifically expressed in the striatum, TREK2 in the cerebellum, and TRAAK in the thalamus.…”

Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels

“…Thus, we conclude that KCNK channels are the likely targets of sanshool action. Indeed, members of this two-pore K + channel subfamily (KCNK2, KCNK3, KCNK9, KCNK10 and KCNK18) have been proposed to set the resting membrane potential of primary afferent sensory neurons, with KCNK18 (TRESK) having the predominant role [19][20][21] .…”

“…In contrast, KCNK18 transcript levels were significantly more abundant (13.1 ± 1.2-fold) in trigeminal ganglia than in CGNs at day 2 or 7, suggesting that this subtype has an important role in mediating sanshool sensitivity of primary sensory neurons. Indeed, among sanshool-sensitive KCNK subtypes, KCNK18 contributes significantly to the background K + current in cultured DRG neurons 20 . Moreover, in situ hybridization histochemistry suggests that KCNK18 transcripts are expressed by a significant fraction of primary sensory neurons 21 .…”

Immunohistochemical colocalization of TREK-1, TREK-2 and TRAAK with TRP channels in the trigeminal ganglion cells

“…In general, these channels are closed at low temperatures (< 30 °C) but are activated by polyunsaturated fatty acid, increasing cellular volume, protons and general anesthetics [5,7]. It has been demonstrated that the mRNAs and proteins of 5 these channels are widely expressed in both the central and peripheral nervous systems using reverse transcriptase-polymerase chain reaction (RT-PCR; [10]), in situ hybridization [13] and immunohistochemistry [4].…”