K2P potassium channels, mysterious and paradoxically exciting

Abstract

New evidence reveals that the common electrolyte disorder hypokalemia can induce K2P1 channels that are normally selective for K+ to break the rules and conduct Na+. This defiant behavior leads to paradoxical depolarization of many cells in the heart, increasing the risk for lethal arrhythmia. The new research resolves a mystery uncovered 50 years ago and bestows an array of new riddles. Here, I discuss how K2P1 might achieve this alchemy--through stable residence of the K+ selectivity filter in a Na+-conductive state between its open and C-inactive configurations--and predict that other K+ channels and environmental stimuli will be discovered to produce the same excitatory misconduct.

Fig. 1

(A) Reversal potentials for K⁺, Na⁺, and RMP of CONTROL HL-1 cells and those expressing K2P1-K²⁷⁴E under normal and hypokalemic conditions. E_K and E_NA were calculated with 4 mM K⁺ and 1 mM K⁺ at 20°C, and RMP for mouse HL-1 cells were under control conditions or expressing K2P1-K²⁷⁴E channels from Ma et al. (5) showing depolarization to −63 mV, with hypokalemia in the latter case. (B) K2P0 subunit and homology model. (Left) Single subunit topology showing M1 to M4 (transmembrane segments 1 to 4) and the two P loops (P1, P2). K²⁷⁴, the residue mutated in K2P1 to avoid sumoylation, is indicated. (Middle) Homology model for the dimeric channel built on the basis of pairs of residues that interact (21) viewed from outside the cell and indicating a K⁺ ion (purple) in the pore shows bilateral symmetry with a fourfold symmetric selectivity filter. One subunit is colored in purple, and the other is blue. The P1 pore helices are in yellow, and P2 pore helices are in green. (Right) Side view of domain I of both subunits. (C) Signature sequences of P1 loop and P2 loop in K2P0 (dORK1), K2P1, K2P2, K2P3 (TASK1), K2P9 (TASK3), K2P10 (TREK2), and K2P13 (THIK1). Although most K2P channels have an I in the P1 loop, the T in K2P1 (highlighted yellow) is identified by Ma et al. as important for its ability to undergo dynamic changes in ion selectivity with hypokalemia. Single-letter abbreviations for the amino acids are standard. (D) K2P1-K²⁷⁴E channels are expressed in CHO cells, and external K⁺ decreased from 5 mM to nominally no K⁺ (0K). Changes in RMP (ΔE_rev) reveal rapid hyperpolarization (phase 1) followed by slow paradoxical depolarization (phase 2) [from Fig. 6A in (5)]. (E) Three classes of KcsA filter structure determined with the lower activation gate in the open configuration from (57). (Left) The filter with 4 K⁺ binding sites conducts K⁺ (K flux). (Middle) The intermediate state shows three K⁺-binding sites in the filter and is proposed in this essay to be similar to the Na⁺-conductive state in K2P1-K²⁷⁴E with hypokalemia (Na⁺ flux proposed). (Right) The nonconducting, C-type inactivated filter shows two K⁺-binding sites.