Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

Abstract

TWIK-related K 1 1 (TREK1) potassium channels are members of the two-pore domain potassium channel family and contribute to background potassium conductances in many cell types, where their activity can be regulated by a variety of physiologic and pharmacologic mediators. amine] enhance the activity of TREK1 currents, and we show that BL-1249 is the most potent of these compounds. Alternative translation initiation produces a shorter, N terminus truncated form of TREK1 with a much reduced open probability and a proposed increased permeability to sodium compared with the longer form. We show that both forms of TREK1 can be activated by fenamates and that a number of mutations that affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. Furthermore, fenamates produce a marked enhancement of current through the shorter, truncated form of TREK1 and reveal a K 1 -selective channel, like the long form. These results provide insight into the mechanism of TREK1 channel activation by fenamates, and, given the role of TREK1 channels in pain, they suggest a novel analgesic mechanism for these compounds.

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

“…BL-1249, a fenamate-like compound, and ML67-33, a dihydroacridine analog, activate TREK1, TREK2, and TRAAK and their isoforms with various N-ter lengths (30,35). For those compounds that are not targeting a unique TREK subunit, TREK/TRAAK heteromerization has only a moderate influence as illustrated by the intermediate sensitivity of TREK1/TRAAK heterodimers to ML67 compared with TREK1 or TRAAK homodimers.…”

“…For TREK/TRAAK channels, heteromerization comes in addition to the molecular diversity generated by AS and ATI that already affect conductance (25), ion selectivity (26), and pharmacology (35). Single-channel properties of TREK1 and TREK2 channel have been extensively studied over the past decade (29).…”

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

“…These compounds have been shown to upor down-regulate the activity of a number of ion channels [38], including TREK1 channels, where they act to enhance current [91,99]. BL-1249, another fenamate-like structure and a putative activator of TREK1-like currents in human bladder myocytes [93] also activated TREK1 channels (Fig.…”

“…The N-terminus truncated form gives rise to a current with a much reduced open probability and a collapsed selectivity filter with both a reduced potassium selectivity [61,74,94,100] and a measurable permeability to sodium [94]. Treatment with both DEPC and fenamates, substantially enhances current through the Nterminus truncated form of the channel, and, interestingly, measurements of the reversal potential in the presence of these compounds reveal that the enhanced currents have become highly K selective [99,100]. Thus, the action of these compounds on the N-terminus truncated form of TREK1 would act to hyperpolarise and decrease the excitability of the neurons they were expressed in, complementing action on the longer form of TREK1.…”

“…BL-1249, another fenamate-like structure and a putative activator of TREK1-like currents in human bladder myocytes [93] also activated TREK1 channels (Fig. 3, also [16,99]). The enhancement of TREK1 current by fenamates is occluded by mutations E306A and W275S (and several other mutations, which alter channel gating, see Figs.…”