I always tell my students in my endocrinology class that the whole system is based on control and specificity. Many of the sessions I attended related to these 2 important concepts in endocrine maintenance of homeostasis.
Building a better mousetrap
As I mentioned in my day 1 post, G protein coupled receptors (GPCR) are among the biggest drug targets and represent an opportunity to develop many more therapeutics, especially in the endocrine system. However, to do that requires a full understanding of their signaling mechanisms. Dr. Jean-Pierre Vilardaga presented on “Non-cannonical signaling of the parathyoid hormone receptor”. For context, here’s the canonical signaling pathway:
From Friedman and Goodman, American Journal of Physiology – Renal Physiology, 2006, 290:F975-F984
Dr. Vilardaga showed that cAMP response (as seen on the left in the figure) has markedly different lengths of time depending on the ligand used to activate the receptor. In fact, he was able to show that cAMP continued to be present 30 minutes after the start of PTH treatment, long after all of the receptor had been internalized, but the same was not true using PTHrP to stimulate the receptor. How is this possible? It turns out that signaling continued on the internalized endosome, and only when the endosome became sufficiently acidified to cause ligand release the signaling was terminated. So what you might ask? There is a novel form of hypocalcemia caused by a change in PTH where it cannot stay bound as long in the endosome. The maximal cAMP is the same but the prolonged signal is absent. This raises the possibility that novel ligands that cause extended cAMP production might be useful in treating these patients.
Dr. Debra Kendall then spoke about allosteric biased modulators of the CB1 receptor. Dr. Kendall used a picture of an iceberg on one of her slides, which I thought was a great analogy for GPCRs- a little is seen on the surface of the cell, but there is a whole lot going on underneath the surface! Dr. Kendall made a great argument for why allosteric regulators (ones that don’t bind to the active site, but rather to an alternate site on the receptor may prove better for developing therapeutics: they can be receptor subtype selective, can have more pharmacore diversity, decreased toxicity or side effects, enhanced specificity for their targets as well as functional specificity (biased agonism) to really fine tune pharmacological responses. She presented the example of rimonabant as a case where an orthostatic regulator (antagonist) of CB1 worked, but had many side effects. CB1 is the cannabinoid receptor (yes, like cannabis) and as you have heard from friends (as Dr. Kendall pointed out, she was sure none of us had experience with this) stimulation of the CB1 receptor by delta 9-THC causes feelings of hunger. The idea was to use an antagonist of the receptor to treat obesity, but in some patients it causes depression and suicide. Coupled with an allosteric regulator it might be safe to use because you can get greater control and specificity.
Posterized
One of the great things about a meeting like ICE/ENDO is the opportunity to learn and make connections. I have a student interested in polymorphisms of the glucocorticoid receptor (I am too, but it is not my main research topic) so I used the opportunity to visit posters related to glucocorticoid hypersensitivity. Posters are a terrific, informal opportunity to talk to people and share ideas.
Paradigm shifts
Molecular mechanisms of glucocorticoid feedback was discussed by Dr. Bob Spencer. The basics are still true: as cortisol is produced in the adrenal gland it goes to the hypothalamus and anterior pituitary to inhibit the synthesis and release of hormones that stimulate the adrenal gland. cortisol acts through its receptor, a nuclear hormone receptor. Or does it? When is a glucocorticoid receptor not a glucocorticoid receptor? When it is on the membrane. I’ll pause while you consider that……There has been evidence for membrane bound estrogen receptors, and it seemed inevitable that a membrane bound cortisol receptor would be found. Still, this continues to complicate and challenge those of us who teach endocrinology. How much do we include in our lectures? Given limited time and focus of students, it seems the most effective approach is to give students the “canonical” pathways and then challenge the most eager to delve deeper.
Another paradigm shift was the idea that cortisol synthesis is regulated by ACTH and comes from the adrenal cortex. However, as Dr. Brian Walker showed, the peripheral conversion of cortisone to cortisol creates as much cortisol daily as de novo synthesis. Peripheral conversion is a great topic in control and specificity because it helps regulate the activity of hormones in different tissues. However, the fact that it creates as much hormone as the adrenal cortex makes on question what site(s) of synthesis are the most important and how can they become targets for therapeutics?
The last day of the conference lies ahead so expect more updates tomorrow!
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