PubMed · 13637092
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A G HILLS. 1959. Selective hypoaldosteronism.. https://doi.org/10.1016/0002-9343(59)90272-4
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In addition to the well-known genomic action of aldosterone, resulting in delayed effect (1-2 h), a very rapid nongenomic effect (1-2 min) of aldosterone has been recognized recently. The nongenomic action pathway of aldosterone involves: signal perception by protein membrane receptors, induction of the synthesis of messenger molecules such as cAMP, IP3, and DAG, and a change of Ca2+ concentration in the cell cytosol. The target of these rapid responses are also ion channels and exchangers. The nongenomic mechanisms of aldosterone action cooperate with its genomic action in some instances.
Acute nitric oxide (NO) inhibits angiotensin II (ANG II)-stimulated aldosterone synthesis in zona glomerulosa (ZG) cells. In this study, we investigated the effects of chronic administration of NO on the ANG II receptor type 1 (AT1) expression and aldosterone synthesis. ZG cells were treated daily with DETA NONOate (10(-4) M), an NO donor, for 0, 12, 24, 48, 72, and 96 h. Chinese hamster ovary (CHO) cells, stably transfected with the AT1B receptor, were used as a positive control. Western blot analysis indicated that AT1 receptor expression was decreased as a function of time of NO administration in both CHO and ZG cells. ANG II binding to its receptors was determined by radioligand binding. NO treatment of ZG cells for 96 h resulted in a decrease in ANG II binding compared with control. The receptor density was decreased to 1,864 +/- 129 fmol/mg protein from 3,157 +/- 220 fmol/mg protein (P < 0.005), but the affinity was not changed (1.95 +/- 0.22 vs. 1.88 +/- 0.21 nM). Confocal Raman microspectroscopy and immunocytochemistry both confirmed that the expression of AT1 receptors in ZG cells decreased with chronic NO administration. In addition, chronic NO administration also decreased the expression of cholesterol side-chain cleavage enzyme in ZG cells and inhibited ANG II- and 25-hydroxycholesterol-stimulated aldosterone synthesis in ZG cells. This study demonstrates that chronic administration of NO inhibits aldosterone synthesis in ZG cells by downregulation of the expression of both AT1 receptors and cholesterol side-chain cleavage enzyme.
We have investigated the functional consequences of three naturally occurring amino acid substitutions of the human mineralocorticoid receptor (hMR). These mutations are located in the DNA-binding domain and the ligand-binding domain (LBD) and are associated with autosomal dominant or sporadic type I pseudohypoaldosteronism. All mutant receptors bound specifically to glucocorticoid-responsive elements but presented modified transcriptional properties. The DNA-binding domain mutant G633R, which possesses a normal affinity for a glucocorticoid-responsive element, displayed altered interaction with, and a reduced dissociation rate from, DNA. Its intracellular localization in the absence of hormone was predominantly nuclear in comparison with predominant cytoplasmic location of hMR. Hormone-dependent nuclear cluster formation was comparable to wild-type hMR. These results and the three-dimensional modeling of the interaction of R633 with DNA suggest that altered interaction dynamics with DNA as well as modified intracellular localization may be responsible for submaximal transcriptional potency of hMR. Two LBD mutations, Q776R and L979P, were also investigated. Our data confirm the fundamental role of amino acid Q776 for anchoring the C3 ketone group of steroids in the ligand-binding pocket. Analysis of LBD conformation of mutant P979 demonstrates the relevance of hydrophobic interactions in the extreme C-terminal tail of the hMR for the correct ligand-binding competent state of the receptor. Our data underline the importance of studying naturally occurring mutants to identify crucial residues involved in hMR function.