Q. I have a question about the secretion of aldosterone that I haven’t been able to figure out by searching online or looking in books (maybe I’m looking in the wrong places!). My question stems from my understanding that aldosterone is one of the end products in the pathway starting with cholesterol.  We learned from you, and other professors too, that aldosterone secretion isn’t really dependent on ACTH but more on angiotensin II, but I guess my confusion is due to the fact that ACTH is responsible for converting cholesterol to pregnenolone which then can go on to produce the aldosterone, cortisol, and androgens we need.  In a nutshell, why doesn’t aldosterone secretion depend on ACTH?  If you could help me fill in some blanks, that would be great!

A. That’s a great question! It is a bit confusing. If ACTH stimulates the initial conversion of cholesterol to pregnenolone, then why shouldn’t all the end products go up?!

There are actually several things that stimulate aldosterone production/release. The two major regulators are angiotensin II and potassium. ACTH, other POMC peptides, sodium, vasopressin, dopamine, atrial natriuretic peptide, beta-adrenergic agents, serotonin and somatostatin are minor modulators. They have some effect on aldosterone but it’s negligible compared to angiotensin II and potassium.

With regard to angiotensin II and ACTH, it’s possible that these substances act on different parts of the aldosterone synthesis pathway (see the diagram above). Some sources say angiotensin II stimulates production of all of the enzymes used in the synthesis of aldosterone, others say it just acts on the first and last enzymes, and still others say it just on the last enzyme (aldosterone synthase). Same goes for ACTH.

Another difference between the two is more of a biochemistry thing, if you can stay awake for it. Angiotensin II and ACTH exert their effects using different cell-signaling pathways. Angiotensin II binds to G-protein coupled receptors, activating phospholipase C, which hydrolyzes PIP2 to IP3, which releases intracellular calcium ions, which activates protein kinase A. ACTH, on the other hand, binds to the cell-surface melanocortin-2 receptor, which activates adenylate cyclase, produces cAMP, and activates Ca2+-calmodulin-dependent protein kinase (CaMK) and diacylglycerol-dependent protein kinase C (PKC). Maybe these pathways have different efficiencies – maybe the G-protein/PKA pathway is simply better at increasing production of the necessary enzymes.

I think for our purposes, though, it’s just important to know that angiotensin II is simply a stronger stimulator of aldosterone synthesis. ACTH is great at stimulating production of cortisol and sex steroids, but it’s not as good at stimulating production of aldosterone. Some of the enzymes in the steroid pathways are the same, but there are several that are unique to each pathway – and ACTH does not appear to be able to stimulate the enzymes unique to the aldosterone pathway very well.