Journal Article

Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension

Bohnen, Michael S., Kass, Robert S., Sampson, Kevin J., Redel-Traub, Gabriel

2022

Overview

Pulmonary arterial hypertension (PAH) is a devastating disease with high morbidity and mortality. Deleterious remodeling in the pulmonary arterial system leads to irreversible arterial constriction and elevated pulmonary arterial pressures, right heart failure, and eventually death. The difficulty in treating PAH stems in part from the complex nature of disease pathogenesis, with several signaling compounds known to be involved (e.g., endothelin-1, prostacyclins) which are indeed targets of PAH therapy. Over the last decade, potassium channelopathies were established as novel causes of PAH. More specifically, loss-of-function mutations in the KCNK3 gene that encodes the two-pore-domain potassium channel KCNK3 (or TASK-1) and loss-of-function mutations in the ABCC8 gene that encodes a key subunit, SUR1, of the ATP-sensitive potassium channel (KATP) were established as the first two potassium channelopathies in human cohorts with pulmonary arterial hypertension. Moreover, voltage-gated potassium channels (Kv) represent a third family of potassium channels with genetic changes observed in association with PAH. While other ion channel genes have since been reported in association with PAH, this review focuses on KCNK3, KATP, and Kv potassium channels as promising therapeutic targets in PAH, with recent experimental pharmacologic discoveries significantly advancing the field.

• Publisher: MDPI AG,MDPI
• Subject: ABCC8 / ABCC8 gene / Care and treatment / Channelopathies - drug therapy / Channelopathies - genetics / channelopathy / Congestive heart failure / Disease / Endothelin 1 / Endothelins / Familial Primary Pulmonary Hypertension - genetics / Genetic aspects / Hemodynamics / Humans / Hypertension / Hypertension, Pulmonary - drug therapy / Hypertension, Pulmonary - genetics / Hypertension, Pulmonary - pathology / Hypoxia / ion channel / KATP Channels - genetics / KCNK3 / Kinases / Lungs / Molecular biology / Morbidity / Mutation / Nerve Tissue Proteins - metabolism / Pathophysiology / Patient outcomes / pharmacology / Physiological aspects / Potassium / Potassium channels / Potassium channels (inwardly-rectifying) / Potassium Channels, Tandem Pore Domain - genetics / Potassium Channels, Voltage-Gated / Prostaglandins I / Pulmonary Arterial Hypertension / Pulmonary arteries / Pulmonary hypertension / Review / Therapeutic applications / Therapeutic targets / Veins & arteries