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

Abstract

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.

Farnesol-Like Endogenous Sesquiterpenoids in Vertebrates: The Probable but Overlooked Functional “Inbrome” Anti-Aging Counterpart of Juvenile Hormone of Insects?

“…This indicates that not only the overall structure of SERCAs has been very well conserved in evolution, but that the binding site of thapsigargin on the SERCAs has also been conserved. De Loof ( 20 ) argued that this binding site of sesquiterpenoids on the endoplasmic reticulum functions as a third type/family of receptors that complements the much better documented plasma membrane receptors and nuclear receptors for (some types) of hormonal ligands.…”

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

“…Although the final outcome is that the intracellular Ca 2+ concentration must be kept very low, particularly in the resting condition of cells, such an outcome can be reached in many different combinations of causal agents. [21] This variability not only yields the outcome that all cells of the body differ in their Ca 2+ homeostasis system, but that such difference also holds at the organismal level. This is the essence of the Calcigender concept as first formulated by De Loof [22]: males and females, and by extrapolation all gender forms differ in their Ca 2+ -homeostasis which means that there probably are as many gender forms with their specific behavior and physiology as there are sexually reproducing individuals in a species [1].…”

The evolution of “Life”: A Metadarwinian integrative approach

“…Yet the most toxic pollutant on earth (O 2 not taken into account) is the omnipresent Ca 2+ -ion. This may look strange because we encounter the beneficial aspects of Ca 2+ in our daily life: our calcareous bony skeleton, Ca 2+ -rich milk, the egg shell of birds, and Ca 2+ as a secondary messenger 45,46 . Yet, because above a very low threshold a rise in cytoplasmic Ca 2+ concentration is very toxic as it causes changes in the conformation of some essential macromolecules, in particular proteins.…”