Increased aldosterone secretion has been found in a mouse lacking the KCNE1 gene which codes for a regulatory protein of the KCNQ1 gene product, forming the channel for the outward rectifying delayed K+ current. Abnormalities in proteins regulating the K+ fluxes across membranes may be responsible for aldosterone-secreting adenomas (aldosteronomas) also because K+ channels are involved in cell growth. Normal and adenomatous adrenal samples and NCI-H295 cell line were used to: a) evaluate KCNE1 and KCNQ1 gene expression, b) sequence the full length cDNAs of KCNE1 and both KCNQ1 isoforms. These differently spliced KCNE1 and KCNQ1 mRNAs were expressed in adrenal tissue. In contrast, KCNQ1 isoform 2 mRNA was not expressed in kidney control tissues and NCl-H295 cell line. NCI-H295 cell line also had a significantly lower expression of KCNQ1 isoform 1 mRNA than normal adrenals and aldosteronomas. We did not find any somatic mutations in the coding sequences of both genes. This different expression pattern of KCNQ1 isoforms in NCI-H295 cell line with the lack of the mRNA for the dominant-negative KCNQ1 isoform 2 supports the involvement of voltage-gated K+ channel in cell proliferation.
[Show abstract][Hide abstract] ABSTRACT: Potassium channels control the membrane voltage of aldosterone-producing zona glomerulosa cells. They are responsible for the unique K(+) sensitivity of these cells and are important molecular targets of angiotensin II signaling. Among the 78 pore-forming K(+) channels in human genome only a few are found in adrenal glands. The 2-P-domain K(+) channels TASK1 and TASK3 are strongly expressed in the adrenal cortex and produce a background K(+) conductance, which is pivotal for the regulation of the aldosterone secretion in zona glomerulosa cells. Disruption of the TASK1 gene in mice resulted in an autonomous aldosterone production and caused a remarkable aberrant expression of aldosterone synthase in zona fasciculata cells that normally produce glucocorticoids. After puberty, only in male mice aldosterone production was switched off in the zona fasciculata and regular zonation of aldosterone synthase occurred. In double mutant TASK1(-/-)/TASK3(-/-) mice, also adult male mice displayed primary hyperaldosteronism. Therefore, these knockout mice are interesting models to study mechanisms of autonomous aldosterone production and adrenocortical zonation. These data suggest that modifications of the adrenocortical K(+) conductances could also contribute to autonomic aldosterone production and primary hyperaldosteronism in humans.
Hormone and Metabolic Research 06/2010; 42(6):450-7. DOI:10.1055/s-0029-1243601 · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thyroid hormones T3/T4 participate in the fine tuning of development and performance. The formation of thyroid hormones requires the accumulation of I(-) by the electrogenic Na(+)/I(-) symporter, which depends on the electrochemical gradient across the cell membrane and thus on K(+) channel activity. The present paper explored whether Kcnq1, a widely expressed voltage-gated K(+) channel, participates in the regulation of thyroid function. To this end, Kcnq1 expression was determined by RT-PCR, confocal microscopy, and thyroid function analyzed in Kcnq1 deficient mice (Kcnq1 ( -/- )) and their wild-type littermates (Kcnq1 ( +/+ )). Moreover, Kcnq1 abundance and current were determined in the thyroid FRTL-5 cell line. Furthermore, mRNA encoding KCNQ1 and the subunits KCNE1-5 were discovered in human thyroid tissue. According to patch-clamp TSH (10 mUnits/ml) induced a voltage-gated K(+) current in FRTL-5 cells, which was inhibited by the Kcnq inhibitor chromanol (10 μM). Despite a tendency of TSH plasma concentrations to be higher in Kcnq1 ( -/- ) than in Kcnq1 ( +/+ ) mice, the T3 and T4 plasma concentrations were significantly smaller in Kcnq1 ( -/- ) than in Kcnq1 ( +/+ ) mice. Moreover, body temperature was significantly lower in Kcnq1 ( -/- ) than in Kcnq1 ( +/+ ) mice. In conclusion, Kcnq1 is required for proper function of thyroid glands.
Pflügers Archiv - European Journal of Physiology 10/2010; 461(1):45-52. DOI:10.1007/s00424-010-0890-5 · 4.10 Impact Factor
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