title: Small-Conductance Ca2+-Activated Potassium Channels Negatively Regulate Aldosterone Secretion in Human Adrenocortical Cells.
abstract: Aldosterone, which plays a key role in maintaining water and electrolyte balance, is produced by zona glomerulosa cells of the adrenal cortex. Autonomous overproduction of aldosterone from zona glomerulosa cells causes primary hyperaldosteronism. Recent clinical studies have highlighted the pathological role of the KCNJ5 potassium channel in primary hyperaldosteronism. Our objective was to determine whether small-conductance Ca(2+)-activated potassium (SK) channels may also regulate aldosterone secretion in human adrenocortical cells. We found that apamin, the prototypic inhibitor of SK channels, decreased membrane voltage, raised intracellular Ca(2+) and dose dependently increased aldosterone secretion from human adrenocortical H295R cells. By contrast, 1-Ethyl-2-benzimidazolinone, an agonist of SK channels, antagonized apamin's action and decreased aldosterone secretion. Commensurate with an increase in aldosterone production, apamin increased mRNA expression of steroidogenic acute regulatory protein and aldosterone synthase that control the early and late rate-limiting steps in aldosterone biosynthesis, respectively. In addition, apamin increased angiotensin II-stimulated aldosterone secretion, whereas 1-Ethyl-2-benzimidazolinone suppressed both angiotensin II- and high K(+)-stimulated production of aldosterone in H295R cells. These findings were supported by apamin-modulation of basal and angiotensin II-stimulated aldosterone secretion from acutely prepared slices of human adrenals. We conclude that SK channel activity negatively regulates aldosterone secretion in human adrenocortical cells. Genetic association studies are necessary to determine whether mutations in SK channel subtype 2 genes may also drive aldosterone excess in primary hyperaldosteronism.
authors.affiliation: From the Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science (T.Y., Q.L., Y.-A.M., C.H.) and Department of Oncology, Shanghai Medical College (H.-L.Z.), Fudan University, China; Department of Urology, Fudan University Shanghai Cancer Center, China (H.-L.Z.); and Department of Pharmacology, University of Virginia, Charlottesville (Y.S., P.Q.B.).
authors.forename: Tingting
authors.initials: T
authors.lastname: Yang
authors.affiliation: From the Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science (T.Y., Q.L., Y.-A.M., C.H.) and Department of Oncology, Shanghai Medical College (H.-L.Z.), Fudan University, China; Department of Urology, Fudan University Shanghai Cancer Center, China (H.-L.Z.); and Department of Pharmacology, University of Virginia, Charlottesville (Y.S., P.Q.B.).
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhang
authors.affiliation: From the Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science (T.Y., Q.L., Y.-A.M., C.H.) and Department of Oncology, Shanghai Medical College (H.-L.Z.), Fudan University, China; Department of Urology, Fudan University Shanghai Cancer Center, China (H.-L.Z.); and Department of Pharmacology, University of Virginia, Charlottesville (Y.S., P.Q.B.).
authors.forename: Qingnan
authors.initials: Q
authors.lastname: Liang
authors.affiliation: From the Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science (T.Y., Q.L., Y.-A.M., C.H.) and Department of Oncology, Shanghai Medical College (H.-L.Z.), Fudan University, China; Department of Urology, Fudan University Shanghai Cancer Center, China (H.-L.Z.); and Department of Pharmacology, University of Virginia, Charlottesville (Y.S., P.Q.B.).
authors.forename: Yingtang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: From the Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science (T.Y., Q.L., Y.-A.M., C.H.) and Department of Oncology, Shanghai Medical College (H.-L.Z.), Fudan University, China; Department of Urology, Fudan University Shanghai Cancer Center, China (H.-L.Z.); and Department of Pharmacology, University of Virginia, Charlottesville (Y.S., P.Q.B.).
authors.forename: Yan-Ai
authors.initials: YA
authors.lastname: Mei
authors.affiliation: From the Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science (T.Y., Q.L., Y.-A.M., C.H.) and Department of Oncology, Shanghai Medical College (H.-L.Z.), Fudan University, China; Department of Urology, Fudan University Shanghai Cancer Center, China (H.-L.Z.); and Department of Pharmacology, University of Virginia, Charlottesville (Y.S., P.Q.B.).
authors.forename: Paula Q
authors.initials: PQ
authors.lastname: Barrett
authors.affiliation: From the Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science (T.Y., Q.L., Y.-A.M., C.H.) and Department of Oncology, Shanghai Medical College (H.-L.Z.), Fudan University, China; Department of Urology, Fudan University Shanghai Cancer Center, China (H.-L.Z.); and Department of Pharmacology, University of Virginia, Charlottesville (Y.S., P.Q.B.). clhu@fudan.edu.cn.
authors.forename: Changlong
authors.initials: C
authors.lastname: Hu
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000378:metabolism*; D000704:Analysis of Variance; D000804:Angiotensin II / Q000008:administration & dosage; D001030:Apamin / Q000008:administration & dosage; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012494:Sampling Studies
chemical_list: D002120:Calcium Channel Agonists; D015221:Potassium Channels; D012333:RNA, Messenger; D000804:Angiotensin II; D001030:Apamin; D000450:Aldosterone
keywords: adrenal cortex aldosterone secretion; angiotensin II; apamin; hyperaldosteronism; small-conductance Ca2+-activated potassium channels