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

Autor: Wendy K. Chung, Kevin J. Sampson, Cecile Terrenoire, Robert S. Kass, Michael S. Bohnen, Danilo Roman-Campos, Jack Jnani
Rok vydání: 2017
Předmět:
0301 basic medicine
Mutant
Muscle
Smooth
Vascular
Membrane Potentials
Loss of Function Mutation
Chlorocebus aethiops
pulmonary hypertension
Familial Primary Pulmonary Hypertension
ortho-Aminobenzoates
pathophysiology
Original Research
Hydrogen-Ion Concentration
Hyperpolarization (biology)
potassium channels
Potassium channel
Cell biology
Electrophysiology
Phenotype
Hypertension
COS Cells
Cardiology and Cardiovascular Medicine
Heterozygote
Myocytes
Smooth Muscle
Nerve Tissue Proteins
Pulmonary Artery
Transfection
03 medical and health sciences
Potassium Channels
Tandem Pore Domain
Genetics
medicine
Animals
Humans
Homomeric
Arterial Pressure
Genetic Predisposition to Disease
Ion channel
business.industry
Wild type
Ion Channels/Membrane Transport
Membrane hyperpolarization
medicine.disease
Pulmonary hypertension
Chlorobenzoates
030104 developmental biology
Cinnamates
Case-Control Studies
ion channel
Cancer research
Protein Multimerization
pharmacology
business
Zdroj: Repositório Institucional da UNIFESP
Universidade Federal de São Paulo (UNIFESP)
instacron:UNIFESP
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
DOI: 10.1161/jaha.117.006465
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: