Human TWIK-related Acid-Sensitive K+ Channel 1 (TASK1): A Target Enabling Package

The TWIK related acid-sensitive K⁺ channel 1 (TASK-1) belongs to the family of two-pore domain potassium (K_2P) channels. It regulates resting membrane potential and is expressed in cardiomyocytes, neurons and vascular smooth muscle cells. Loss of function mutations in TASK-1 lead to primary pulmonary hypertension type 4 (PPH4) which is often fatal in mid-life (1). We have produced TASK-1 and determined structures of this protein alone and in complex with two highly potent inhibitors, BAY 1000493 and BAY 2341237, with EC₅₀ values of 9.5 nM and 7.6 nM, respectively. We have used a two-electrode voltage clamp assay to measure the effect of mutations in TASK-1 and the effect of inhibitors. The native structure of TASK-1 also allowed us to map the six known disease mutations leading to PPH4.