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

Background Heterozygous loss of function mutations in the KCNK 3 gene cause hereditary pulmonary arterial hypertension ( PAH ). KCNK 3 encodes an acid‐sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells. KCNK 3 is widely expressed in the body, and dimerizes with other KCNK 3 subunits, or the closely related, acid‐sensitive KCNK 9 channel. Methods and Results We engineered homomeric and heterodimeric mutant and nonmutant KCNK 3 channels associated with PAH . Using whole‐cell patch‐clamp electrophysiology in human pulmonary artery smooth muscle and COS 7 cell lines, we determined that homomeric and heterodimeric mutant channels in heterozygous KCNK 3 conditions lead to mutation‐specific severity of channel dysfunction. Both wildtype and mutant KCNK 3 channels were activated by ONO ‐ RS ‐082 (10 μmol/L), causing cell hyperpolarization. We observed robust gene expression of KCNK 3 in healthy and familial PAH patient lungs, but no quantifiable expression of KCNK 9 , and demonstrated in functional studies that KCNK 9 minimizes the impact of select KCNK 3 mutations when the 2 channel subunits co‐assemble. Conclusions Heterozygous KCNK 3 mutations in PAH lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant KCNK 3 channels represent novel therapeutic substrates in PAH . Pharmacological and pH ‐dependent activation of wildtype and mutant KCNK 3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co‐assembly of KCNK 3 with KCNK 9 subunits may provide protection against KCNK 3 loss of function in tissues where both KCNK 9 and KCNK 3 are expressed, contributing to the lung‐specific phenotype observed clinically in patients with PAH because of KCNK 3 mutations.

Abstract licence: CC BY-NC

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