The mega-evolution of life with its three memory systems depends on sender-receiver communication and problem-solving. A narrative review.

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.

Neuropeptides as Regulators of Behavior in Insects.

Neuropeptides are by far the largest and most diverse group of signaling molecules in multicellular organisms. They are ancient molecules important in regulating a multitude of processes. Their small proteinaceous character allowed them to evolve and radiate quickly into numerous different molecules. On average, hundreds of distinct neuropeptides are present in animals, sometimes with unique classes that do not occur in distantly related species. Acting as neurotransmitters, neuromodulators, hormones, or growth factors, they are extremely diverse and are involved in controlling growth, development, ecdysis, digestion, diuresis, and many more physiological processes. Neuropeptides are also crucial in regulating myriad behavioral actions associated with feeding, courtship, sleep, learning and memory, stress, addiction, and social interactions. In general, behavior ensures that an organism can survive in its environment and is defined as any action that can change an organism's relationship to its surroundings. Even though the mode of action of neuropeptides in insects has been vigorously studied, relatively little is known about most neuropeptides and only a few model insects have been investigated. Here, we provide an overview of the roles neuropeptides play in insect behavior. We conclude that multiple neuropeptides need to work in concert to coordinate certain behaviors. Additionally, most neuropeptides studied to date have more than a single function.

The endocrine system controlling sexual reproduction in animals: Part of the evolutionary ancient but well conserved immune system?

Drastic changes in hormone titers, in particular of steroid hormones, are intuitively interpreted as necessary and beneficial for optimal functioning of animals. Peaks in progesterone- and estradiol titers that accompany the estrus cycle in female vertebrates as well as in ecdysteroids at each molt and during metamorphosis of holometabolous insects are prominent examples. A recent analysis of insect metamorphosis yielded the view that, in general, a sharp rise in sex steroid hormone titer signals that somewhere in the body some tissue(s) is undergoing programmed cell death/apoptosis. Increased steroid production is part of this process. Typical examples are ovarian follicle cells in female vertebrates and invertebrates and the prothoracic gland cells, the main production site of ecdysteroids in larval insects. A duality emerges: programmed cell death-apoptosis is deleterious at the cellular level, but it may yield beneficial effects at the organismal level. Reconciling both opposites requires reevaluating the probable evolutionary origin and role of peptidic brain hormones that direct steroid hormone synthesis. Do e.g. Luteinizing Hormone in vertebrates and Prothoracicotropic Hormone (PTTH: acting through the Torso receptor) in insects still retain an ancient role as toxins in the early immune system? Does the functional link of some neuropeptides with Ca(2+)-induced apoptosis make sense in endocrine archeology? The endocrine system as a remnant of the ancient immune system is undoubtedly counterintuitive. Yet, we will argue that such paradigm enables the logical framing of many aspects, the endocrine one inclusive of both male and female reproductive physiology.

Epigenetics and locust life phase transitions.

Insects are one of the most successful classes on Earth, reflected in an enormous species richness and diversity. Arguably, this success is partly due to the high degree to which polyphenism, where one genotype gives rise to more than one phenotype, is exploited by many of its species. In social insects, for instance, larval diet influences the development into distinct castes; and locust polyphenism has tricked researchers for years into believing that the drastically different solitarious and gregarious phases might be different species. Solitarious locusts behave much as common grasshoppers. However, they are notorious for forming vast, devastating swarms upon crowding. These gregarious animals are shorter lived, less fecund and transmit their phase characteristics to their offspring. The behavioural gregarisation occurs within hours, yet the full display of gregarious characters takes several generations, as does the reversal to the solitarious phase. Hormones, neuropeptides and neurotransmitters influence some of the phase traits; however, none of the suggested mechanisms can account for all the observed differences, notably imprinting effects on longevity and fecundity. This is why, more recently, epigenetics has caught the interest of the polyphenism field. Accumulating evidence points towards a role for epigenetic regulation in locust phase polyphenism. This is corroborated in the economically important locust species Locusta migratoria and Schistocerca gregaria. Here, we review the key elements involved in phase transition in locusts and possible epigenetic regulation. We discuss the relative role of DNA methylation, histone modification and small RNA molecules, and suggest future research directions.

The essence of female-male physiological dimorphism: differential Ca2+-homeostasis enabled by the interplay between farnesol-like endogenous sesquiterpenoids and sex-steroids? The Calcigender paradigm.

Ca(2+) is the most omnipresent pollutant on earth, in higher concentrations a real threat to all living cells. When [Ca(2+)]i rises above 100 nM (=resting level), excess Ca(2+) needs to be confined in the SER and mitochondria, or extruded by the different Ca(2+)-ATPases. The evolutionary origin of eggs and sperm cells has a crucial, yet often overlooked link with Ca(2+)-homeostasis. Because there is no goal whatsoever in evolution, gametes did neither originate "with the purpose" of generating a progeny nor of increasing fitness by introducing meiosis. The explanation may simply be that females "invented the trick" to extrude eggs from their body as an escape strategy for getting rid of toxic excess Ca(2+) resulting from a sex-hormone driven increased influx into particular cells and tissues. The production of Ca(2+)-rich milk, seminal fluid in males and all secreted proteins by eukaryotic cells may be similarly explained. This view necessitates an upgrade of the role of the RER-Golgi system in extruding Ca(2+). In the context of insect metamorphosis, it has recently been (re)discovered that (some isoforms of) Ca(2+)-ATPases act as membrane receptors for some types of lipophilic ligands, in particular for endogenous farnesol-like sesquiterpenoids (FLS) and, perhaps, for some steroid hormones as well. A novel paradigm, tentatively named "Calcigender" emerges. Its essence is: gender-specific physiotypes ensue from differential Ca(2+)-homeostasis enabled by genetic differences, farnesol/FLS and sex hormones. Apparently the body of reproducing females gets temporarily more poisoned by Ca(2+) than the male one, a selective benefit rather than a disadvantage.

The essence of insect metamorphosis and aging: electrical rewiring of cells driven by the principles of juvenile hormone-dependent Ca(2+)-homeostasis.

In holometabolous insects the fall to zero of the titer of Juvenile Hormone ends its still poorly understood "status quo" mode of action in larvae. Concurrently it initiates metamorphosis of which the programmed cell death of all internal tissues that actively secrete proteins, such as the fat body, midgut, salivary glands, prothoracic glands, etc. is the most drastic aspect. These tissues have a very well developed rough endoplasmic reticulum, a known storage site of intracellular Ca(2+). A persistent high [Ca(2+)]i is toxic, lethal and causal to apoptosis. Metamorphosis becomes a logical phenomenon if analyzed from: (1) the causal link between calcium toxicity and apoptosis; (2) the largely overlooked fact that at least some isoforms of Ca(2+)-ATPases have a binding site for farnesol-like endogenous sesquiterpenoids (FRS). The Ca(2+)-ATPase blocker thapsigargin, like JH a sesquiterpenoid derivative, illustrates how absence of JH might work. The Ca(2+)-homeostasis system is concurrently extremely well conserved in evolution and highly variable, enabling tissue-, developmental-, and species specificity. As long as JH succeeds in keeping [Ca(2+)]i low by keeping the Ca(2+)-ATPases pumping, it acts as "the status quo" hormone. When it disappears, its various inhibitory effects are lifted. The electrical wiring system of cells, in particular in the regenerating tissues, is subject to change during metamorphosis. The possibility is discussed that in vertebrates an endogenous farnesol-like sesquiterpenoid, probably farnesol itself, acts as a functional, but hitherto completely overlooked Juvenile anti-aging "Inbrome", a novel concept in signaling.

The mode of action of juvenile hormone and ecdysone: towards an epi-endocrinological paradigm?

In some insect species, two sites of juvenile hormone (JH) synthesis have been reported: the very well documented corpora allata that secrete JH for "general use", and the reproductive system, in particular the male accessory glands, in which the function of the sometimes huge amounts of JH (e.g. in Hyalophora cecropia) remains to be clarified. A recent finding in Schistocerca gregaria, namely that suppression of the ecdysteroid peak preceding a molt by RNAi of the Halloween genes spook, phantom and shade does not impede normal molting, challenges the (never experimentally proven) classical concept that such a peak is causally linked to a molt. Recent developments in epigenetic control of gene expression in both the honey bee and in locusts suggest that, in addition to the classical scheme of hormone-receptor (membrane- and/or nuclear) mode of action, there may be a third way. Upon combining these and other orphan data that do not fit in the commonly accepted textbook schemes, we here advance the working hypothesis that both JH and ecdysone might be important but overlooked players in epigenetic control of gene expression, in particular at extreme concentrations (peak values or total absence). In this review, we put forward how epi-endocrinology can complement classical arthropod endocrinology.

Endocrine archeology: do insects retain ancestrally inherited counterparts of the vertebrate releasing hormones GnRH, GHRH, TRH, and CRF?

Vertebrate releasing hormones include gonadotropin releasing hormone (GnRH), growth hormone releasing hormone (GHRH), corticotropin releasing hormone (CRF), and thyrotropin-releasing hormone (TRH). They are synthesized in the hypothalamus and stimulate the release of pituitary hormones. Here we review the knowledge on hormone releasing systems in the protostomian lineage. We address the question: do insects have peptides that may be phylogenetically related to an ancestral GnRH, GHRH, TRH, and CRF? Such endocrine archeology has become possible thanks to the growing list of fully sequenced genomes as well as to the continuously improving bioinformatic tool set. It has recently been shown that the ecdysozoan (nematodes and arthropods) adipokinetic hormones (AKHs), the lophotrochozoan (annelids and mollusks) GnRHs as well as the protochordate GnRHs are structurally related. The adipokinetic hormone precursor-related peptides (APRPs), in locusts encoded by the same gene that contains the AKH-coding region, have been forwarded as the structural counterpart of GHRH of vertebrates. CRF is relatively well conserved in insects, in which it functions as a diuretic hormone. Members of TRH-receptor family seem to have been conserved in some arthropods, but other elements of the thyroid hormone signaling system are not. A challenging idea is that in insects the functions of the thyroid hormones were taken over by juvenile hormone (JH). Our reconstruction suggests that, perhaps, the ancestral releasing hormone precursors played a role in controlling energy metabolism and water balance, and that releasing hormone functions as present in extant vertebrates were probably secondarily acquired.

The mega-evolution of life depends on sender-receiver communication and problem-solving.

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.

Key role of juvenile hormone in controlling reproductive diapause in females of the Asian lady beetle Harmonia axyridis.

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.

Locust phase polyphenism: Does epigenetic precede endocrine regulation?

The morphological, physiological and behavioural differences between solitarious and gregarious desert locusts are so pronounced that one could easily mistake the two phases as belonging to different species, if one has no knowledge of the phenomenon of phenotypic plasticity. A number of phase-specific features are hormonally controlled. Juvenile hormone promotes several solitarious features, the green cuticular colour being the most obvious one. The neuropeptide corazonin elicits the dark cuticular colour that is typical for the gregarious phase, as well as particular gregarious behavioural characteristics. However, it had to be concluded, for multiple reasons, that the endocrine system is not the primary phase-determining system. Our observation that longevity gets imprinted in very early life by crowding of the young hatchlings, and that it cannot be changed thereafter, made us consider the possibility that, perhaps, epigenetic control of gene expression might be, if not the missing, a primary phase-determining mechanism. Imprinting is likely to involve DNA methylation and histone modification. Analysis of a Schistocerca EST database of nervous tissue identified the presence of several candidate genes that may be involved in epigenetic control, including two DNA methyltransferases (Dnmts). Dnmt1 and Dnmt2 are phase-specifically expressed in certain tissues. In the metathoracic ganglion, important in the serotonin pathway for sensing mechanostimulation, their expression is clearly affected by crowding. Our data urge for reconsidering the role of the endocrine system as being sandwiched in between genetics and epigenetics, involving complementary modes of action.

Culex quinquefasciatus Late Trypsin Biosynthesis Is Translationally Regulated by Trypsin Modulating Oostatic Factor.

Trypsin is a serine protease that is synthesized by the gut epithelial cells of female mosquitoes; it is the enzyme that digests the blood meal. To study its molecular regulation, Culex quinquefasciatus late trypsin was purified by diethylaminoethyl (DEAE), affinity, and C18 reverse-phase high performance liquid chromatography (HPLC) steps, and the N-terminal amino acid sequence was determined for molecular cloning. Five overlapping segments of the late trypsin cDNA were amplified by PCR, cloned, and the full sequence (855 bp) was characterized. Three-dimensional models of the pro-trypsin and activated trypsin were built and compared with other trypsin models. Trypsin modulating oostatic factor (TMOF) concentrations in the hemolymph were determined by ELISA and compared with trypsin activity in the gut after the blood meal. The results showed that there was an increase in TMOF concentrations circulating in the hemolymph which has correlated to the reduction of trypsin activity in the mosquito gut. Northern blot analysis of the trypsin transcripts after the blood meal indicated that trypsin activity also followed the increase and decrease of the trypsin transcript. Injections of different amounts of TMOF (0.025 to 50 µg) decreased the amounts of trypsin in the gut. However, Northern blot analysis showed that TMOF injections did not cause a decrease in trypsin transcript abundance, indicating that TMOF probably affected trypsin translation.

In search for a common denominator for the diverse functions of arthropod corazonin: a role in the physiology of stress?

Corazonin (Crz) is an 11 amino acid C-terminally amidated neuropeptide that has been identified in most arthropods examined with the notable exception of beetles and an aphid. The Crz-receptor shares sequence similarity to the GnRH-AKH receptor family thus suggesting an ancestral function related to the control of reproduction and metabolism. In 1989, Crz was purified and identified as a potent cardioaccelerating agent in cockroaches (hence the Crz name based on "corazon", the Spanish word for "heart"). Since the initial assignment as a cardioacceleratory peptide, additional functions have been discovered, ranging from pigment migration in the integument of crustaceans and in the eye of locusts, melanization of the locust cuticle, ecdysis initiation and in various aspects of gregarization in locusts. The high degree of structural conservation of Crz, its well-conserved (immuno)-localization, mainly in specific neurosecretory cells in the pars lateralis, and its many functions, suggest that Crz is vital. Yet, Crz-deficient insects develop normally. Upon reexamining all known effects of Crz, a hypothesis was developed that the evolutionary ancient function of Crz may have been "to prepare animals for coping with the environmental stressors of the day". This function would then complement the role of pigment-dispersing factor (PDF), the prime hormonal effector of the clock, which is thought "to set a coping mechanism for the night".

Two Undervalued Functions of the Golgi Apparatus: Removal of Excess Ca2+ and Biosynthesis of Farnesol-Like Sesquiterpenoids, Possibly as Ca2+-Pump Agonists and Membrane "Fluidizers-Plasticizers".

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.

PDF receptor signaling in Drosophila contributes to both circadian and geotactic behaviors.

The neuropeptide Pigment-Dispersing Factor (PDF) is a principle transmitter regulating circadian locomotor rhythms in Drosophila. We have identified a Class II (secretin-related) G protein-coupled receptor (GPCR) that is specifically responsive to PDF and also to calcitonin-like peptides and to PACAP. In response to PDF, the PDF receptor (PDFR) elevates cAMP levels when expressed in HEK293 cells. As predicted by in vivo studies, cotransfection of Neurofibromatosis Factor 1 significantly improves coupling of PDFR to adenylate cyclase. pdfr mutant flies display increased circadian arrhythmicity, and also display altered geotaxis that is epistatic to that of pdf mutants. PDFR immunosignals are expressed by diverse neurons, but only by a small subset of circadian pacemakers. These data establish the first synapse within the Drosophila circadian neural circuit and underscore the importance of Class II peptide GPCR signaling in circadian neural systems.

Nature, Calcigender, Nurture: Sex-dependent differential Ca2+ homeostasis as the undervalued third pillar.

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.

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

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.

Intraluminal Farnesol and Farnesal in the Mealworm's Alimentary Canal: An Unusual Storage Site Uncovering Hidden Eukaryote Ca2+-Homeostasis-Dependent "Golgicrine" Activities.

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.

Flip-Flopping Retinal in Microbial Rhodopsins as a Template for a Farnesyl/Prenyl Flip-Flop Model in Eukaryote GPCRs.

Thirty years after the first description and modeling of G protein coupled receptors (GPCRs), information about their mode of action is still limited. One of the questions that is hard to answer is: how do the allosteric changes in the GPCR induced by, e.g., ligand binding in the end activate a G protein-dependent intracellular pathway (e.g., via the cAMP or the phosphatidylinositol signal pathways). Another question relates to the role of prenylation of G proteins. Today's "consensus model" states that protein prenylation is required for the assembly of GPCR-G protein complexes. Although it is well-known that protein prenylation is the covalent addition of a farnesyl- or geranylgeranyl moiety to the C terminus of specific proteins, e.g., α or γ G protein, the reason for this strong covalent binding remains enigmatic. The arguments for a fundamental role for prenylation of G proteins other than just being a hydrophobic linker, are gradually accumulating. We uncovered a dilemma that at first glance may be considered physiologically irrelevant, however, it may cause a true change in paradigm. The consensus model suggests that the only functional role of prenylation is to link the G protein to the receptor. Does the isoprenoid nature of the prenyl group and its exact site of attachment somehow matter? Or, are there valid arguments favoring the alternative possibility that a key role of the G protein is to guide the covalently attached prenyl group to - and it hold it in - a very specific location in between specific helices of the receptor? Our model says that the farnesyl/prenyl group - aided by its covalent attachment to a G protein -might function in GPCRs as a horseshoe-shaped flexible (and perhaps flip-flopping) hydrophobic valve for restricting (though not fully inhibiting) the untimely passage of Ca2+, like retinal does for the passage of H+ in microbial rhodopsins that are ancestral to many GPCRs.

Only two sex forms but multiple gender variants: How to explain?

Are sex and gender interchangeable terms? In classical biology, both are sometimes but not always used on an equal basis for some groups of animals. However, for our own species the Homo sapiens, they are not. A major question is why are there only two types of gametes (sperm- and egg cells), two types of sex steroids, (androgens and estrogens in vertebrates, and two types of ecdysteroids in insects), while the reproduction-related behaviour of the gamete producers displays a much greater variability than just two prominent forms, namely heterosexual males and heterosexual females? It indicates that in addition to a few sex-determining genes ( = the first pillar), other factors play a role. A second possible pillar is the still poorly understood cognitive memory system in which electrical phenomena and its association with the plasma membrane membrane-cytoskeletal complex of cells play a major role (learning, imitation and imprinting). This paper advances a third pillar, that hitherto has been almost completely ignored, namely the cellular Ca2+-homeostasis system, more specifically its sex-specific differences. Differential male-female genetics- and hormone-based Ca2+-homeostasis with effects on gender-related processes has been named Calcigender before. It will be argued that it follows from the principles of Ca2+- physiology and homeostasis that all individuals of a sexually reproducing animal population have a personalized gender behaviour. Thus, subdividing gender-behaviours in hetero-, homo-, bi-, trans- etc. which all result from a differential use of the very same basic physiological principles, is too primitive a system that may yield false sociological interpretations.