The Impact of Heterozygous <i>KCNK3</i> Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

Abstract

Heterozygous <i>KCNK3</i> mutations in PAH lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant KCNK3 channels represent novel therapeutic substrates in PAH. Pharmacological and pH-dependent activation of wildtype and mutant KCNK3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co-assembly of KCNK3 with KCNK9 subunits may provide protection against KCNK3 loss of function in tissues where both <i>KCNK9</i> and <i>KCNK3</i> are expressed, contributing to the lung-specific phenotype observed clinically in patients with PAH because of <i>KCNK3</i> mutations.