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It should be the ultimate goal of any theory of evolution to delineate the contours of an integrative system to answer the question: How does life (in all its complexity) evolve (which can be called mega‐evolution)? But how to plausibly define 'life'? My answer (1994–2023) is: 'life' sounds like a noun, but denotes an activity, and thus is a verb. Life (L) denotes nothing else than the total sum (∑) of all acts of communication (transfer of information) (C) executed by any type of senders–receivers at all their levels (up to at least 15) of compartmental organization: L = ∑C. The 'communicating compartment' is better suited to serve as the universal unit of structure, function and evolution than the cell, the smallest such unit. By paying as much importance to communication activity as to the Central Dogma of molecular biology, a wealth of new insights unfold. The major ones are as follows. (1) Living compartments have not only a genetic memory (DNA), but also a still enigmatic cognitive and an electrical memory system (and thus a triple memory system). (2) Complex compartments can have up to three types of progeny: genetic descendants/children, pupils/learners and electricians. (3) Of particular importance to adaptation, any act of communication is a problem‐solving act because all messages need to be decoded. Hence through problem‐solving that precedes selection, life itself is the driving force of its own evolution (a very clever but counterintuitive and unexpected logical deduction). Perhaps, this is the 'vital force' philosopher and Nobel laureate (in 1927) Henri Bergson searched for but did not find. [ABSTRACT FROM AUTHOR]

BACKGROUND The Asian lady beetle Harmonia axyridis is an important predator of several agricultural pests, including aphids and whiteflies, and thus can contribute to pest management. Commercial viability as a pest control method requires that the beetle can be mass‐reared, and that workable conditions for extended shelf‐life can be guaranteed. One of the features of Harmonia's life cycle is that it enters diapause in the adult stage when the length of the photophase starts shortening in late summer. Reduction of juvenile hormone (JH) titer has been demonstrated to be the common endocrine mechanism inducing reproductive diapause in insects. However, whether H. axyridis enters diapause dependent on JH shutdown and how the JH level is regulated before diapause remains unknown. RESULTS: Like in other insects, the absence of JH triggers the induction and maintenance of reproductive diapause in H. axyridis, indicated by JH measurements and the knockdown of an intracellular JH receptor methoprene‐tolerant (Met). Methoprene, a JH analog, significantly reversed diapause into reproduction via Met. Combined with RNA‐sequencing and RNA interference, we also demonstrated that JH biosynthesis rather than the JH degradation pathway determines the reduction of JH titer in diapausing females. CONCLUSION: Our results reveal the vital role of JH in regulating reproductive diapause in female H. axyridis. Harmonia axyridis diapause could thus be manipulated by targeting JH production and JH signaling. © 2021 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The extensive literature dealing with the Golgi system emphasizes its role in protein secretion and modification, usually without specifying from which evolutionary ancient cell physiological necessity such secretion originated. Neither does it specify which functional requirements the secreted proteins must meet. From a reinterpretation of some classical and recent data gained mainly, but not exclusively, from (insect) endocrinology, the view emerged that the likely primordial function of the rough endoplasmic reticulum (RER)–Golgi complex in all eukaryotes was not the secretion of any type of protein but the removal of toxic excess Ca2+ from the cytoplasm. Such activity requires the concurrent secretion of large amounts of Ca2+-carrying/transporting proteins acting as a micro-conveyor belt system inside the RER–Golgi. Thus, (fitness increasing) protein secretion is subordinate to Ca2+ removal. Milk with its high content of protein and Ca2+ (60–90 mM vs. 100 nM in unstimulated mammary gland cells) is an extreme example. The sarco(endo)plasmatic reticulum Ca2+-ATPases (SERCAs) and SPCA1a Ca2+/Mn2+ transport ATPases are major players in Ca2+ removal through the Golgi. Both are blocked by the sesquiterpenoid thapsigargin. This strengthens the hypothesis (2014) that endogenous farnesol-like sesquiterpenoids (FLSs) may act as the long sought for but still unidentified agonist (s) for Ca2+-pumps in both the ER and Golgi. A second putative function also emerges. The fusion of both the incoming and outgoing transport vesicles, respectively, at the cis - and trans - side of Golgi stacks, with the membrane system requiring high flexibility and fast self-closing of the involved membranes. These properties may—possibly partially—be controlled by endogenous hydrophobic membrane "fluidizers" for which FLSs are prime candidates. A recent reexamination of unexplained classical data suggests that they are likely synthesized by the Golgi itself. This game-changing hypothesis is endorsed by several arguments and data, some of which date from 1964, that the insect corpus allatum (CA), which is the major production site of farnesol-esters, has active Golgi systems. Thus, in addition to secreting FLS, in particular juvenile hormone(s), it also secretes a protein(s) or peptide(s) with thus far unknown function. This paper suggests answers to various open questions in cell physiology and general endocrinology. [ABSTRACT FROM AUTHOR]

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]

Farnesol, the sesquiterpenoid precursor of the six presently known insect juvenile hormones (JHs) was for the first time chemically identified in 1961, not in JH synthesizing glands or whole body extracts, but in excrements of the mealworm Tenebrio molitor. This finding was thought to be irrelevant and remained unexplored. In 1970, it was reported that the fall to zero of the JH titer in both prediapausing adults and in last instar larvae of the Colorado potato beetle causes severe malfunctioning of the Golgi system in the fat body, among various other effects. This endomembrane system in the cytoplasm resides at the intersection of the secretory, lysosomal, and endocytic pathways and is required for the processing of secretory proteins. Why the Golgi needs farnesol-like endogenous sesquiterpenoids (FLS) for its proper functioning has also never been further investigated. In 1999, farnesol was found to be a natural endogenous ligand for particular types of voltage-gated Ca2+ channels in mammalian cells, a finding that also remained undervalued. Only since 2014 more attention has been paid to the functional research of the "noble unknown" farnesol, in particular to its Ca2+-homeostasis-related juvenilizing and anti-apoptotic activities. Here, we introduce the term "Golgicrine activity" that addresses the secretory activity of the RER-Golgi system from its role in Ca2+-homeostasis rather than from its conventional role in mere protein secretion. Golgicrine activity attributes the so far forgotten role of farnesol-like sesquiterpenoids in proper Golgi functioning, and unites the endocrine, exocrine and enterocrine functions of these sesquiterpenoids. This out of the box view may open novel perspectives for the better understanding of particular inflammatory bowel diseases and of neurodegenerative diseases as well, because the early initiation of Alzheimer's disease may possibly result from malfunctioning of the mevalonate-farnesol-cholesterol biosynthetic pathway and thus might be a farnesol- and Ca2+-homeostasis-dependent Golgicrine issue. [ABSTRACT FROM AUTHOR]

Changes in titers of Juvenile Hormone(s) [JH(s)], the "status quo" hormone, and the molting hormone 20-OH-Ecdysone (20E), since 2019 also referred to as the anabolic steroid of plant origin named Vitamin D1, are key players in insect metamorphosis. Ecdysterone 20E is a water- and lipid soluble compound. Juvenile hormone (JH) occurs in six sesquiterpenoids isoforms, which are esters of farnesol, all highly hydrophobic compounds with high affinity for cell membranes. They are synthesized by the mevalonate biosynthetic pathway found in uniand multicellular eukaryotes, including the evolutionarily ancient zooflagellates (Opisthokonta), which are presumed as ancestral to all animals. The mevalonate pathway of insects does not include the enzyme squalene synthase. Hence, they cannot biosynthesize cholesterol, the precursor for the biosynthesis of (ecdy)steroid hormones. Cholesterol and plant steroids are utilized as vitamins by insects. What is the mechanism that drastically reduces the titer of JH causing metamorphosis in holometabolous insects? How can the absence of JH cause drastic changes in insect development? Could this be caused by the collapse of Ca-homeostasis after the binding sites for endogenous sesquiterpenoids on Ca channels, Ca2+ pumps, etc. are no longer occupied? What is the exact mode of action of 20E/vitamin D1, not only in insects but also in humans? Are JH and 20E antagonists, as was already postulated during the 1960s? Do both hormones compete for the same receptors? We argue that this is not the case and offer an alternative explanation. First, not only the nuclear, but also the membrane receptors of JH and 20E differ. Second, both hormones seem to antagonistically control Ca2+-homeostasis of target cells. Farnesol, an agonist of JH-biosynthesis, is a potent inhibitor of specific voltage-gated Ca2+- channels, and thus inhibits the influx of Ca2+ in target cells. In contrast, upon activation of its membrane GPCR, 20E facilitates the influx of Ca2+ into the cytoplasm. In essence, hormonepropelled changes in intracellular free Ca2+-concentration, [Ca2+]i, are the primordial driving force of complete metamorphosis. This hypothesis explains genomic and non-genomic effects that occur at high or low hormonal titers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

After many years of sometimes heated discussions, the problem regarding the relative importance of two classical dogmas of the Nature (genes and sex-steroid hormones) versus Nurture (education, teaching-learning etc.) debate, is still awaiting a conclusive solution. Males and females differ in only a few (primordial) genes as is well documented by genomic analyses. However, their sexand gender-specific behavior and physiology is nevertheless profoundly different, even if they grew up in a similar (educational) environment. By extending the "Calcigender-concept", originally formulated in 2015, to the simplistic binary Nature versus Nurture concept, a novel framework showing that the sex-steroid hormone-dependent intracellular Calcium concentration is an important third factor may emerge. Although the principles of animal physiology and evolution strongly stress the fact that Nature is always dominant, Nurture can, to a limited extent, play a mitigating role. [ABSTRACT FROM AUTHOR]

Darwin's theory of evolution with focus on the origin of new species was formulated in an era in which the principles of genetics, biochemistry, physiology, communication etc. were not an issue. Numerous revolutionary new insights have since been gained. 1. The 'sender-receiver communicating compartment", a classical but still valuable concept, is better suited than 'the cell' to serve the role of universal unit of structure and function, 'the cell' being the smallest such unit; 2. Not only genetic, but non-genetic mechanisms as well contribute to variability that can be passed onto the next generation; 3. Natural selection, the almost unanimously accepted universal driving force of evolution, is itself the result of preceding problem-solving activity enabled by the principles of communication; 4. A logically deduced, unambiguous definition of 'Life' has been published so that now the key question can shift from Darwin's formulation towards "How does 'Life', with its many aspects, change in the course of time"? Communication activity represents the very heart of being alive, thus of 'Life itself'. In digital-era wording, living entities are hardware-software double continua. This paper advances an easily teachable change in paradigm, namely that evolution concerns ever changing complexes of signalling pathways, chemical and other, that occasionally yield both new species and additional (at least 16) levels of communication. This approach complements the genetic basis of the New Synthesis with several as yet undervalued mechanisms from physiology and development. In particular, 'the universal selfgenerated electrical dimension of cells' and Lamarckism deserve an upgrade. [ABSTRACT FROM AUTHOR]

Literature on the question whether the juvenile stage of vertebrates is hormonally regulated is scarce. It seems to be intuitively assumed that this stage of development is automated, and does not require any specific hormone(s). Such reasoning mimics the state of affairs in insects until it was shown that surgical removal of a tiny pair of glands in the head, the corpora allata, ended larval life and initiated metamorphosis. Decades later, the responsible hormone was found and named "juvenile hormone" (JH) because when present, it makes a larva molt into another larval stage. JH is a simple ester of farnesol, a sesquiterpenoid present in all eukaryotes.Whereas vertebrates do not have an anatomical counterpart of the corpora allata, their tissues do contain farnesol-like sesquiterpenoids (FLS). Some display typical JH activity when tested in appropriate insect bioassays. Some FLS are intermediates in the biosynthetic pathway of cholesterol, a compound that insects and nematodes (DEcdysozoa) cannot synthesize by themselves. They ingest it as a vitamin. Until a recent (2014) reexamination of the basic principle underlying insect metamorphosis, it had been completely overlooked that the Ca2+-pump (SERCA) blocker thapsigargin is a sesquiterpenoid that mimics the absence of JH in inducing apoptosis. In our opinion, being in the juvenile state is primarily controlled by endogenous FLS that participate in controlling the activity of Ca2+-ATPases in the sarco(endo)plasmic reticulum (SERCAs), not only in insects but in all eukaryotes. Understanding the control mechanisms of being in the juvenile state may boost research not only in developmental biology in general, but also in diseases that develop after the juvenile stage, e.g., Alzheimer's disease. It may also help to better understand some of the causes of obesity, a syndrome that holometabolous last larval insects severely suffer from, and for which they found a very drastic but efficient solution, namely metamorphosis. [ABSTRACT FROM AUTHOR]

It is logical to define "Life" prior to uncovering the mechanisms that allow changes, e.g. short (development) and long (evolution). In retrospect, however, the opposite happened. Darwin, Wallace, Lamarck, and other pioneers who lived when modern science was in its infancy, formulated their ideas on evolution asking "how new species come into existence", and not "How does 'Life' evolve?". It led to revolutionary concepts of Common Descent and Natural Selection. It took until the advent of communication sciences in the 20th century that the computer/ digital vocabulary was gradually embraced by many disciplines, as well as in daily language. Concurrently, substantial progress was also realized in the majority of the exact sciences and in the humanities. Therefore the question - asked in 2014 - whether the classical neo-Darwinism-based evolutionary theory needs a rethink was then justified and appropriate (too early for some, too late for others). This paper, summarizes the gradual development of my ideas why a switch in paradigm, from "The cell is the basic building block structure and function of all living compartments" to "a sender-receiver alternative" offers a novel and better perspective. Indeed, it introduces a new communicationbased potent concept and approach for analyzing various as yet undervalued aspects in the evolution of "Life". Of particular importance is the view that any act of communication is a problem-solving act because all messages are coded and need to be decoded before they can yield a response., (Copyright: © 2022 by Fabrizio Serra editore, Pisa · Roma.)

The extensive literature dealing with the Golgi system emphasizes its role in protein secretion and modification, usually without specifying from which evolutionary ancient cell physiological necessity such secretion originated. Neither does it specify which functional requirements the secreted proteins must meet. From a reinterpretation of some classical and recent data gained mainly, but not exclusively, from (insect) endocrinology, the view emerged that the likely primordial function of the rough endoplasmic reticulum (RER)-Golgi complex in all eukaryotes was not the secretion of any type of protein but the removal of toxic excess Ca 2+ from the cytoplasm. Such activity requires the concurrent secretion of large amounts of Ca 2+ -carrying/transporting proteins acting as a micro-conveyor belt system inside the RER-Golgi. Thus, (fitness increasing) protein secretion is subordinate to Ca 2+ removal. Milk with its high content of protein and Ca 2+ (60-90 mM vs. 100 nM in unstimulated mammary gland cells) is an extreme example. The sarco(endo)plasmatic reticulum Ca 2+ -ATPases (SERCAs) and SPCA1a Ca 2+ /Mn 2+ transport ATPases are major players in Ca 2+ removal through the Golgi. Both are blocked by the sesquiterpenoid thapsigargin. This strengthens the hypothesis (2014) that endogenous farnesol-like sesquiterpenoids (FLSs) may act as the long sought for but still unidentified agonist (s) for Ca 2+ -pumps in both the ER and Golgi. A second putative function also emerges. The fusion of both the incoming and outgoing transport vesicles, respectively, at the cis - and trans - side of Golgi stacks, with the membrane system requiring high flexibility and fast self-closing of the involved membranes. These properties may-possibly partially-be controlled by endogenous hydrophobic membrane "fluidizers" for which FLSs are prime candidates. A recent reexamination of unexplained classical data suggests that they are likely synthesized by the Golgi itself. This game-changing hypothesis is endorsed by several arguments and data, some of which date from 1964, that the insect corpus allatum (CA), which is the major production site of farnesol-esters, has active Golgi systems. Thus, in addition to secreting FLS, in particular juvenile hormone(s), it also secretes a protein(s) or peptide(s) with thus far unknown function. This paper suggests answers to various open questions in cell physiology and general endocrinology., (Copyright © 2020 De Loof and Schoofs.)

Farnesol, the sesquiterpenoid precursor of the six presently known insect juvenile hormones (JHs) was for the first time chemically identified in 1961, not in JH synthesizing glands or whole body extracts, but in excrements of the mealworm Tenebrio molitor . This finding was thought to be irrelevant and remained unexplored. In 1970, it was reported that the fall to zero of the JH titer in both prediapausing adults and in last instar larvae of the Colorado potato beetle causes severe malfunctioning of the Golgi system in the fat body, among various other effects. This endomembrane system in the cytoplasm resides at the intersection of the secretory, lysosomal, and endocytic pathways and is required for the processing of secretory proteins. Why the Golgi needs farnesol-like endogenous sesquiterpenoids (FLS) for its proper functioning has also never been further investigated. In 1999, farnesol was found to be a natural endogenous ligand for particular types of voltage-gated Ca 2+ channels in mammalian cells, a finding that also remained undervalued. Only since 2014 more attention has been paid to the functional research of the "noble unknown" farnesol, in particular to its Ca 2+ -homeostasis-related juvenilizing and anti-apoptotic activities. Here, we introduce the term "Golgicrine activity" that addresses the secretory activity of the RER-Golgi system from its role in Ca 2+ -homeostasis rather than from its conventional role in mere protein secretion. Golgicrine activity attributes the so far forgotten role of farnesol-like sesquiterpenoids in proper Golgi functioning, and unites the endocrine, exocrine and enterocrine functions of these sesquiterpenoids. This out of the box view may open novel perspectives for the better understanding of particular inflammatory bowel diseases and of neurodegenerative diseases as well, because the early initiation of Alzheimer's disease may possibly result from malfunctioning of the mevalonate-farnesol-cholesterol biosynthetic pathway and thus might be a farnesol- and Ca 2+ -homeostasis-dependent Golgicrine issue., (Copyright © 2019 De Loof and Schoofs.)

After many years of sometimes heated discussions, the problem regarding the relative importance of two classical dogmas of the Nature (genes and sex-steroid hormones) versus Nurture (education, teaching-learning etc.) debate, is still awaiting a conclusive solution. Males and females differ in only a few (primordial) genes as is well documented by genomic analyses. However, their sex- and gender-specific behavior and physiology is nevertheless profoundly different, even if they grew up in a similar (educational) environment. By extending the "Calcigender-concept", originally formulated in 2015, to the simplistic binary Nature versus Nurture concept, a novel framework showing that the sex-steroid hormone-dependent intracellular Calcium concentration is an important third factor may emerge. Although the principles of animal physiology and evolution strongly stress the fact that Nature is always dominant, Nurture can, to a limited extent, play a mitigating role.

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 Ca 2+ channels in some mammalian cell types. The tandem mevalonate pathway and Ca 2+ channels originated early in eukaryotic evolution, and has since been well conserved, "promoting" it as a ubiquitous player in Ca 2+ 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 Ca 2+ 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 Ca 2+ -passage through some types of canonical Ca 2+ 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 Ca 2+ -sensitive transcription factors. Some theoretical and practical considerations for possible applications in a medical context will be discussed.