Ion occupancy of the selectivity filter controls opening of a cytoplasmic gate in the K_2P channel TALK-2.

ABSTRACT: Two-pore domain K⁺ (K_2P) channel activity was previously thought to be controlled primarily via a selectivity filter (SF) gate. However, recent crystal structures of TASK-1 and TASK-2 revealed a lower gate at the cytoplasmic pore entrance. Here, we report functional evidence of such a lower gate in the K_2P channel K2P17.1 (TALK-2, TASK-4). We identified compounds (drugs and lipids) and mutations that opened the lower gate allowing the fast modification of pore cysteine residues. Surprisingly, stimuli that directly target the SF gate (i.e., pH_e., Rb⁺ permeation, membrane depolarization) also opened the cytoplasmic gate. Reciprocally, opening of the lower gate reduced the electric work to open the SF via voltage driven ion binding. There

SUBMITTER: Neelsen LC 

PROVIDER: S-EPMC11364775 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature