Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

作者：Scholl, Ute I.^*; Abriola, Laura; Zhang, Chengbiao; Reimer, Esther N.; Plummer, Mark; Kazmierczak, Barbara I.; Zhang, Junhui; Hoyer, Denton; Merkel, Jane S.; Wang, Wenhui; Lifton, Richard P.^*

来源：Journal of Clinical Investigation, 2017, 127(7): 2739-2750.

DOI：10.1172/JCI91733

• MOTOR STIMULATING ACTIVITY
• N-SUBSTITUTED DERIVATIVES
• PLACEBO-CONTROLLED TRIAL
• SOMATIC MUTATIONS
• 8,9-ANHYDROERYTHROMYCIN-A 6,9-HEMIACETAL
• CYSTIC-FIBROSIS
• DOUBLE-BLIND
• PREVALENCE
• METAANALYSIS
• EXPRESSION

Aldosterone-producing adenomas (APAs) are benign tumors of the adrenal gland that constitutively produce the salt-retaining steroid hormone aldosterone and cause millions of cases of severe hypertension worldwide. Either of 2 somatic mutations in the potassium channel KCNJ5 (G151R and L168R, hereafter referred to as KCNJ5(MUT)) in adrenocortical cells account for half of APAs worldwide. These mutations alter channel selectivity to allow abnormal Na+ conductance, resulting in membrane depolarization, calcium influx, aldosterone production, and cell proliferation. Because APA diagnosis requires a difficult invasive procedure, patients often remain undiagnosed and inadequately treated. Inhibitors of KCNJ5(MUT) could allow noninvasive diagnosis and therapy of APAs carrying KCNJ5 mutations. Here, we developed a high-throughput screen for rescue of KCNJ5(MUT)-induced lethality and identified a series of macrolide antibiotics, including roxithromycin, that potently inhibit KCNJ5(MUT), but not KCNJ5(WT). Electrophysiology demonstrated direct KCNJ5(MUT) inhibition. In human aldosterone-producing adrenocortical cancer cell lines, roxithromycin inhibited KCNJ5(MUT)-induced induction of CYP11B2 (encoding aldosterone synthase) expression and aldosterone production. Further exploration of macrolides showed that KCNJ5(MUT) was similarly selectively inhibited by idremcinal, a macrolide motilin receptor agonist, and by synthesized macrolide derivatives lacking antibiotic or motilide activity. Macrolide-derived selective KCNJ5(MUT) inhibitors thus have the potential to advance the diagnosis and treatment of APAs harboring KCNJ5(MUT).

• 出版日期2017-6-30
• 单位徐州医科大学