Pulmonary arterial hypertension (PAH) results from impaired blood flow through the pulmonary arterial system, leading to increased mean pulmonary arterial pressure, and ultimately right heart failure. A deadly disease, PAH yields a 15% mortality rate within the first year. At the cellular level, proliferation and contraction of pulmonary artery smooth muscle cells (PASMCs), endothelial dysfunction, and adventitial thickening contribute varying degrees to PAH. However, PAH remains a poorly treated, lethal disease, with an incomplete understanding of disease pathogenesis. Our research group has applied genomic studies to uncover TASK-1 potassium channel loss-of-function mutations as a novel cause of PAH. TASK-1, a background potassium channel that is constitutively open in physiologic conditions, is expressed throughout the body in many organs and tissues. In pulmonary arteries, TASK-1 helps to maintain the resting membrane potential of the smooth muscle cells. TASK-1 inactivates, or closes, at more acidic extracellular pH values, and further activates (opens) at alkaline pH. Past research suggests that TASK-1 inhibition leads to depolarization of PASMCs. I wish to test the hypothesis that TASK-1 mutations may thus lead to excessive PASMC depolarization, cell contraction, resultant pulmonary arterial constriction, leading ultimately to PAH. Along with the discovery of PAH-associated TASK-1 mutations, we found that a compound previously described as a phospholipase A2 inhibitor, ONO-RS-082, rescues function of wild-type (WT) and some mutant TASK-1 channels. This finding underscores the value of research into TASK-1 as a potential avenue for medical therapy, as TASK-1 may represent a novel pharmacological target for PAH in particular, and pulmonary hypertension in general. I will first study specific PAH-associated TASK-1 mutations expressed in COS-7 cells and human PASMCs under heterozygous TASK-1 conditions to mimic a PAH patient genotype. Using whole-cell patch clamp, pharmacological, and biochemical assays, I will determine whether the TASK-1 mutants yield dominant negative loss-of-function by different mechanisms, and uncover how the cellular electrophysiological profile of TASK-1 mutation results in a PAH disease phenotype, but no systemic illness, despite TASK-1 expression in many organs of the human body. To translate my cellular findings into physiological and medical relevance, I will test the hypothesis that TASK-1 activators, such as ONO-RS-082, lead to dilation of pulmonary arteries, using pressure myography on dissected rat pulmonary arteries. I will use a pulmonary hypertensive rat disease model vs. wild-type rats, to understand whether our putative TASK-1 activator has medical relevance in its ability to dilate pulmonary arteries in disease. The research proposed would advance the study of TASK-1 greatly, and help us better understand the possibility for novel therapeutics for PAH via TASK-1 activation.