![]() ![]() The channels are grouped as either SF-gated/NCA-activated or HBC (helix-bundle crossing)-gated. ( D) Bars ± S.E.M represent fold change of outward currents upon exchange of intracellular K + by Rb + for K 2P and BK Ca channels (+100 mV), for hERG, K v1.1, K v1.5, K v3.1 channels (+60 mV) and K ir1.1 channels (+40 mV). THexA inhibition represents currents at +100 mV ± 50 μM NS11021 (compound structure depicted n ≥ 11). ( C) BK Ca channel currents (voltage steps from a holding potential of -80 mV to +100 mV (zero Ca 2+)) in i-o patches ± the indicated compounds. PD-118057 dose-response curves represent normalized tail currents ± 1 μM TPenA that produced 91 ± 1 % inhibition of basal currents (n ≥ 6). ( B) hERG channel currents (voltage steps from -80 mV to +60 mV) in i-o patches ± the indicated compounds arrows indicate peak tail current amplitudes at -100 mV. BL-1249 (compound structure depicted) dose-response curves represent currents at +40 mV ± 5 μM THexA that produced 77 ± 6 % inhibition of basal currents (n ≥ 8). ( A) Representative TREK-1 channel currents recorded in inside-out (i-o) patches evoked by voltage ramps in the absence (basal) and presence of the indicated compounds. Negatively charged activators (NCAs) open SF-gated K + channels via a similar site. Together, these data suggest that these negatively charged activators (termed NCAs) (BL-1249, PD-118057 and NS11021) act on a gating mechanism that is shared among these different classes of K + channels, and that their action involves a site that overlaps with the conserved QA L +-binding site located below the SF filter. Furthermore, extended screening with BL-1249 also revealed potent activation of several other K 2P channels (TREK-2, TRAAK, TALK-1, TALK-2, THIK-1 and THIK-2 fig. Likewise, all these activators reduced the QA L +-mediated inhibition in these different K + channels ( Fig. In all cases the compound-mediated effect was effectively antagonized by large quaternary ammonium ions (QA L +) such as tetra-pentyl-ammonium (TPenA) or tetra-hexyl-ammonium (THexA) that are known to block K + channels at a site immediately below the inner entrance to the SF ( 16) ( Fig. This suggests they may not target channel specific activation mechanisms and may instead share a common mechanism. 1C) whose activation curve is strongly shifted to more negative voltages ( fig. However, application of these compounds to their respective ‘non-target’ channels revealed an unexpected poly-pharmacology: all three openers displayed equal efficiency in opening TREK-1 channels ( Fig. Here we identify a common mechanism for drug-induced channel opening that bypasses these physiological activation mechanisms in SF-gated K + channels.įor the mechanosensitive K 2P channels TREK-1 and TREK-2, the voltage-gated hERG and the Ca 2+-activated BK Ca channels, a series of small molecule activators all harboring a negatively charged group (tetrazole or carboxylate) have been proposed to act as selective channel openers (i.e. In voltage-gated hERG channels, both mechanisms co-exist with voltage opening the lower gate, but rapid inactivation occurring through closure of the SF gate ( 11, 12). However, despite this complexity, these activation pathways seem to converge on the two principal mechanisms known to gate K + channels open - dilation of the ‘lower’ gate at the intracellular pore entrance employed by inwardly-rectifying (K ir) ( 5) and voltage-gated (K v) K + channels ( 6), and activation of the selectivity filter (SF) gate used by most two-pore domain K + (K 2P) channels ( 4, 7, 8) and Ca 2+-activated (BK Ca, Slo) K + channels ( 9, 10). Consequently, screening efforts have identified a number of agents that open various different types of K + channels ( 2) presumably by targeting their respective channel-specific activation mechanisms.ĭistinct structural mechanisms enable K + channels to respond to a plethora of physiological stimuli including voltage, temperature, mechanical force, and various second messengers, such as ATP, Ca 2+, and H +, as well as bioactive lipids such as PIP 2 and arachidonic acid ( 3, 4). Dampening cellular electrical activity by pharmacological activation of specific types of K + channels has therapeutic potential for the treatment of a variety of disease states including epilepsy, arrhythmias, vascular constriction or various pain conditions ( 1, 2).
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