Mode of Action of Farnesol, the "Noble Unknown" in Particular in Ca2+ Homeostasis, and Its Juvenile Hormone-Esters in Evolutionary Retrospect.

Arnold De Loof,Liliane Schoofs

doi:10.3389/fnins.2019.00141

Abstract

Farnesol, the sesquiterpenoid precursor of insect juvenile hormones (JH) that itself has JH activity, existed already long before animals and their hormones came into being. Although it is omnipresent in all eukaryotes, this molecule remains a “noble unknown” in cell physiology. It is neither documented as a hormone nor as another type of signaling molecule. To date, its function as an intermediate in the synthesis of squalene-cholesterol-steroids in chordates/vertebrates, and of the insect/arthropod JHs, esters of farnesol, in the mevalonate biosynthetic pathway is assumed to be the only one. This assumption neglects that already two decades ago, farnesol has been shown to be a potent endogenous inhibitor of N-type voltage-gated Ca2+ channels in some mammalian cell types. The tandem mevalonate pathway and Ca2+ channels originated early in eukaryotic evolution, and has since been well conserved, “promoting” it as a ubiquitous player in Ca2+ homeostasis in all eukaryotes. This paper accentuates how this drastic change in thinking gained momentum after the discovery by Paroulek and Sláma that the huge amounts of JH I in male accessory glands of the Cecropia moth, are actually synthesized in these glands themselves and not in the corpora allata, the hitherto assumed unique synthesis site of such compounds. In addition, MAG-JHs have no hormonal- but an exocrine function. Here we hypothesize that MAG-JHs may function in protecting the spermatozoa against toxic Ca2+ concentrations, and in enabling their flagellum to undulate. They may do so by acting through membrane receptors. Our novel paradigm assigns to farnesol/JHs a function of flexible hydrophobic molecular valves for restricting untimely Ca2+-passage through some types of canonical Ca2+channels, using covalently bound farnesyl- or geranyl-geranyl group attachment as well as GPCRs-G proteins all containing a prenyl group. The high rotatable bond count, and their horseshoe-shape are instrumental to their valve function. In our paradigm, Met/Tai and Gce, to date generally thought to be the (only) functional (nuclear) receptors for JHs, are classified as probable Ca2+-sensitive transcription factors. Some theoretical and practical considerations for possible applications in a medical context will be discussed.

Highlights

When the chemical nature of insect juvenile hormone was identified in 1968 by Röller and Dahm, the majority of the nowadays well-developed subdisciplines in endocrinology and evolutionary theory were still in their infancy
Farnesol, the precursor of all juvenile hormones (JHs) and itself a compound with moderate JH activity (Wigglesworth, 1969), has been identified already two decades ago, as an endogenous inhibitor of some type of voltage-gated Ca2+ channels that act as their plasma membrane receptor
We found experimental data on the complexity of the Ca2+-homeostasis system in a choanoflagellate

Summary

INTRODUCTION

When the chemical nature of insect juvenile hormone was identified in 1968 by Röller and Dahm, the majority of the nowadays well-developed subdisciplines in endocrinology and evolutionary theory were still in their infancy. Farnesol, the precursor of all juvenile hormones (JHs) and itself a compound with moderate JH activity (Wigglesworth, 1969), has been identified already two decades ago (in some mammalian cell types), as an endogenous inhibitor of some type of voltage-gated Ca2+ channels that act as their plasma membrane receptor (as already cited). This raised as yet unanswered questions as to the cell physiologic archaeology and ancient role of the tandem voltage gated Ca2+-channel-farnesol/FLS.

DISCUSSION

CONCLUSION