From One Site of Insect Juvenile Hormone Synthesis, No Identified Receptors, and a Denomination as "Status Quo Hormone" in the 1960s to Multiple, Sometimes Conflicting, Possibilities to Date.

Juvenile hormones (JHs) are a group of acyclic sesquiterpenoids. They are biosynthesized in the mevalonate biosynthetic pathway as esters of farnesol (F). F is best known as an intermediate in this pathway that is omnipresent in all eukaryotes. Since 2019 it became apparent that F also has an important role on its own, namely in Ca2+- homeostasis, as a receptor of some types of Ca2+-channels in mammals. JHs occur in 6 forms, they are poorly soluble in water, and they regulate many aspects of insect physiology. In 1967, when the chemical structure of the first insect JH (JH I) was published, the corpora allata (CA), which are located in the head, were assumed to be the only site, or source, of JH-synthesis. However, the fact that JH I had not been extracted from active CA but from abdomens of young (maximum 96 hours old) adult male, not female, Cecropia moths, Hyalophora cecropia, with intact CA presented a problem. Given the large amounts of JH present in the extract, which was called "golden oil", this JH had apparently started to accumulate during metamorphosis. How did JH I end up in the abdomen, why was it quantitatively sex- and tissue-specific, and what was its function(s) and mode of action? First, in 1976 it turned out, unexpectedly, that not the fat body as initially presumed, but the accessory sex glands (MAGs) acted as the exclusive repository for the huge amounts of JHs, namely 2.1 μg JH I and 0.3 μg JH II. It was then thought that the JHs had been synthesized by the CA, although presumed to be inactive during metamorphosis. After a long period with moderate progress, in 2014, it became established MAG-JHs are not synthesized in the CA, but by the MAGs themselves, that they not released into the hemolymph, but secreted, along with other MAG secretions, into the genital duct system of the female during copulation. MAG-JH was named "exocrine JH", to functionally distinguish it from "endocrine/hormonal JH" that is chemically identical but synthesized by the CA in young larvae and adults. Furthermore, the focus on how JH exert its functions also shifted considerably in the past decade, namely towards molecular genetic approaches, in particular to its nuclear- and membrane receptors. Concurrently, the importance of Ca2+- homeostasis and of the hydrophobic properties of JH also got more attention. In the pioneering days of insect endocrinology, JH had become known as the "master-" and as the "status quo hormone", denominations that continue to be used in some textbooks to date. What did status quo originally mean, and how did its meaning gradually evolve towards one of today's interpretations that says that "keeping the cytoplasmic free Ca2+ concentration below the toxicity limit of Ca2+ (when rising above 100 nanomolar) for a longer period of time" is a, if not the key issue. Indeed, without such very low free Ca2+ in the cytoplasm, the well documented secondary signaling systems such as "Ca2+ as a secondary messenger", "Ca2+-induced Ca2+-release from intracellular storage sites (e.g., the endoplasmic reticulum)", and "Control of the activity of some enzyme systems which are anchored in endomembranes, and which can be inhibited by a high intraluminal Ca2+ concentration" could not become functional. Maintaining such low free cytoplasmic concentration of Ca2+ in resting cells is indeed a big challenge because the average Ca2+ concentration, in aqueous extracellular environments, is thousands of times higher (about 2 millimolar or higher). After optimal conditions for maintaining low Ca2+-conditions can be realized, a second level of activity for JHs can start. It is mediated through intranuclear targets/receptors. In our model, extranuclear (membrane-) and nuclear targets/receptors (e.g., transcription factors) are necessarily complementary. [ABSTRACT FROM AUTHOR]