Question

To answer the following questions you may use any resource however the material is primarily derived from Introduction to Bioinformatics, Lesk 2014. In particular refer to chapter 5 page 211-213 on using phylogeny to trace the evolution of vertebrate steroid receptors.

1. Describe how researchers located the residues responsible for the loss of aldosterone affinity?

Answer 1

Aldosterone plays an important role in cardiovascular health. Aldosterone is crucial for sodium conservation in the kidney, salivary glands, sweat glands and colon. Aldosterone promotes active sodium transport and excretion of potassium via the mineralocorticoid receptor (MR). Aldosterone is synthesized exclusively in the zona glomerulosa of the adrenal gland. Destruction or dysfunction of the adrenal gland in conditions such as primary adrenal insufficiency, congenital adrenal hypoplasia, isolated mineralocorticoid deficiency, acquired secondary aldosterone deficiency (hyporeninemic hypoaldosteronism), acquired primary aldosterone deficiency and inherited enzymatic defects in aldosterone biosynthesis cause clinical symptoms and laboratory characteristics owing to aldosterone deficiency.

Pseudohypoaldosteronism is an aldosterone resistance syndrome i.e. a condition due to insensitivity of target tissues to aldosterone. All human steroid hormones are derived from cholesterol. Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex through four enzymes, cholesterol desmolase (CYP11A1), 21-hydroxylase (CYP21A2), aldosterone synthase (CYP11B2) and 3β-hydroxysteroid dehydrogenase (3β-HSD).

In a healthy individual, the renin-angiotensin-aldosterone system functions without interference. It helps to regulate and control blood pressure levels naturally. Sometimes, individuals can have too-high or too-low amounts of aldosterone, and it can both impact the aldosterone function.

Individuals with high levels of aldosterone have a condition known as hyperaldosteronism, and this is typically caused by small, benign tumors on the adrenal glands. Hyperaldosteronism can cause high blood pressure, low potassium levels and an abnormal increase in blood volume because of the way the hormone affects the body.

In the same ways it is also possible to have low levels of aldosterone. Primary adrenal insufficiency, a disease that causes a general loss of adrenal function, can be a cause. Patients with primary adrenal insufficiency causing low levels of aldosterone may experience low blood pressure, increased potassium levels, and lethargy.

Genetic mutations can also affect the production of aldosterone. Patients with this rare genetic disorder will experience symptoms similar to primary adrenal insufficiency but the symptoms are typically less severe.

The research about Aldosterone has collected a lot amount of information about its physiological role that this steroid hormone plays in solute homeostasis and also about its pathophysiological role in aspects of human disease. The dysfunction in aldosterone production or signaling is not only the main cause of a small number of salt-handling conditions but also it contributes to more clinical conditions such as essential hypertension, heart failure, and the insulin resistance (“metabolic”) syndrome.

Burning issues include further understanding of the role of aldosteronein nonepithelial tissues (such as the heart where little is known of detailed cellular mechanisms of action), and further definition of the physiological and clinical relevance of the fast nongenomic effects of aldosterone. In research directed at the basic mechanism of aldosteroneaction, two areas stand out: The first is to further understand the specific nuclear events that distinguish signaling through MR versus GR both at the level of agonist⧸antagonist binding and via coactivator⧸corepressor–receptor interactions. This may lead to specific tissue-selective approaches to aldosterone⧸MR signaling modulation or blockade. The second is to expand the list of specific aldosterone target genes, and to characterize these targets biochemically and physiologically (particularly in the context of genetargeting approaches).

Sometimes considered the poor unexciting cousin of the steroid hormone family, aldosterone is now clearly an important factor in the pathophysiology of some common clinical conditions, and of increasing interest as a focus for basic research. There is a solid foundation of knowledge to build on in designing improved treatments for conditions related to aldosterone excess or abnormal activity of its signaling pathways. The advent of pharmacogenomics and tissue-selective agonists⧸antagonists provides exciting future prospects for targeted therapies for the treatment of aldosterone dysfunction.