UC Berkeley

Potassium two-pore domain (K2P) family ion channels are increasingly appreciated as important electrogenic sensors that are used by diverse cell types including neurons, cardiomyocytes, and epithelial cells. The activity of these channels can be activated up to one-hundred fold by diverse physical and chemical stimuli including pH, intracellular calcium, temperature, phospholipids and fatty acids, volatile anesthetics, and membrane tension. In addition to this “stimulus gated” activity, channels in this family also have a basal “leak gated” activity that drives the cellular resting membrane close to the potassium ion reversal potential in the absence of their respective stimuli. While the structural basis of closed states and certain “stimulus gated” open states have been previously determined, the structural basis of a “leak gated” open state in K2P channels is unknown. Here, we show the physical basis for basal “leak gated” activity of the mechanosensitive K2P family ion channel TRAAK, and propose a gating model that includes both “leak gated” and “stimulus gated” openings. Next, we identify the structural basis of intracellular and extracellular alkaline pH “stimulus gated” activation in the acid-sensitive K2P family ion channel TASK2. We observe structural similarities between the “leak gated” structure of TRAAK and other K2P channel structures, including TASK2. This observation supports a general mechanism for “leak gated” activity in K2P family ion channels.