Month: September 2022

NEW FAST COTRANSFECTION ASSAY. “This “reverse endocrinology” concept allowed for high-throughput screens of natural, synthetic, and xenobiotic ligands that required less-than-micromolar concentrations to unearth which receptors might mediate their signaling.” https://lnkd.in/dXjCCgQ View in LinkedIn

FIRST ORPHAN ASSIGNED. “Applying the reverse endocrinology approach to the retinoid X receptor (RXR) led to the identification of the first endogenous ligand for an orphan nuclear receptor (9-cis retinoic acid, a metabolite of vitamin A), establishing RXR as the founding member of the “adopted” orphan class.” https://lnkd.in/dXjCCgQ View in LinkedIn

HIGHER HANGING FRUIT. “Classic endocrinology identified thyroid hormone and vitamins A and D as vital factors; however, these hormones bind their receptors with high affinity, similar to the classic steroid hormones. In contrast, the reverse endocrinology strategy allowed for the identification of lower-affinity endogenous ligands that were derived from dietary lipids.” https://lnkd.in/dXjCCgQ View in LinkedIn

LOW AFFINITY TARGETS. “A major role of the receptors for these lipid-derived ligands was to maintain the homeostasis of the ligands themselves. Thus, the natural ligands being identified turned out to be predictive hallmarks of the physiologic pathways being regulated by their cognate receptors.” https://lnkd.in/dXjCCgQ View in LinkedIn

FIRST BIG CONCEPT UNLEASHED. “The discovery of RXR and its ligand resulted in the genesis of two prodigious concepts in the nuclear receptor field. First, in revealing the existence of a previously unknown signaling pathway, it provided a proof of principle that precipitated a wave of research aimed at linking other orphan receptors to specific ligands.” (RXR = retinoid receptor). https://lnkd.in/dXjCCgQ View in LinkedIn

SECOND BIG CONCEPT UNLEASHED. “Second, it led to the discovery of RXR heterodimerization with these adopted orphan receptors, thereby defining a novel feature of multiple intertwined signaling pathways.” (RXR = retinoid receptor). https://lnkd.in/dXjCCgQ View in LinkedIn

TRANSFORMATIVE CONCEPT. “We refer to the discovery of heterodimerization as the “RXR Big Bang” because its explosive impact gave rise to a wave of discovery, including entirely new physiologic signaling pathways.” (RXR = retinoid receptor). https://lnkd.in/dXjCCgQ View in LinkedIn

DRUG DISCOVERY TARGETS. “Orphan nuclear receptors have now transitioned through the tipping point as therapeutic targets in the treatment of human disease.” https://lnkd.in/dXjCCgQ View in LinkedIn

SO ENDS this lovely 2014 review of the historical highpoints in nuclear receptor discoveries. Mostly driven by the development of powerful methods, including gene isolation and reverse transfection, these led the way to big concepts that allowed significant discoveries to be made by shining their light into the darkness of the cell. This story, especially the Endogenous opioid superfamily, is one of the most endearing histories in biochemistry. View in LinkedIn

STIMULANTS. "A 2006 study based on a 2002 survey indicated that 7 million Americans have misused these medicines. So this is a long-standing problem." http://www.forbes.com/sites/matthewherper/2012/06/10/the-questions-about-adhd-drugs-the-new-york-times-didnt-ask/#dddf7982f07a View in LinkedIn