Rapid Non-genomic Actions Research Articles

Corticosteroids and the brain

The brain is continuously exposed to varying levels of adrenal corticosteroid hormones such as corticosterone in rodents and cortisol in humans. Natural fluctuations occur due to ultradian and circadian variations or are caused by exposure to stressful situations. Brain cells express two types of corticosteroid receptors, i.e. mineralocorticoid and glucocorticoid receptors, which differ in distribution and affinity. These receptors can mediate both rapid non-genomic and slow gene-mediated neuronal actions. As a consequence of these factors, natural (e.g. stress-induced) shifts in corticosteroid level are associated with a complex mosaic of time- and region-dependent changes in neuronal activity. A series of experiments in humans and rodents have revealed that these time- and region-dependent cellular characteristics are also reflected in distinct cognitive patterns after stress. Thus, directly after a peak of corticosteroids, attention and vigilance are increased, and areas involved in emotional responses and simple behavioral strategies show enhanced activity. In the aftermath of stress, areas involved in higher cognitive functions become activated allowing individuals to link stressful events to the specific context and to store information for future use. Both phases of the brain's response to stress are important to face a continuously changing environment, promoting adaptation at the short as well as long term. We argue that a balanced response during the two phases is essential for resilience. This balance may become compromised after repeated stress exposure, particularly in genetically vulnerable individuals and aggravate disease manifestation. This not only applies to psychiatric disorders but also to neurological diseases such as epilepsy.

Differential expression of vitamin D-associated enzymes and receptors in brain cell subtypes

Accumulating evidence indicates that the active form of vitamin D, 1,25(OH)2D3, can be considered as a neurosteroid. However, the cerebral expression of vitamin D-associated enzymes and receptors remains controversial. With the idea of carrying out a comparative study in mind, we compared the transcript expression of Cyp27a1, Cyp27b1, Cyp24a1, Vdr and Pdia3 in purified cultures of astrocytes, endothelial cells, microglia, neurons and oligodendrocytes. We observed that endothelial cells and neurons can possibly transform the inactive cholecalciferol into 25(OH)D3. It can then be metabolised into 1,25(OH)2D3, by neurons or microglia, before being transferred to astrocytes where it can bind to VDR and initiate gene transcription or be inactivated when in excess. Alternatively, 1,25(OH)2D3 can induce autocrine or paracrine rapid non-genomic actions via PDIA3 whose transcript is abundantly expressed in all cerebral cell types. Noticeably, brain endothelial cells appear as a singular subtype as they are potentially able to transform cholecalciferol into 25(OH)D3 and exhibit a variable expression of Pdia3, according to 1,25(OH)2D3 level. Altogether, our data indicate that, within the brain, vitamin D may trigger major auto-/paracrine non genomic actions, in addition to its well documented activities as a steroid hormone.

Membrane progesterone receptor beta (mPR\u03b2/Paqr8) promotes progesterone-dependent neurite outgrowth in PC12 neuronal cells via non-G protein-coupled receptor (GPCR) signaling

Recently, sex steroid membrane receptors garnered world-wide attention because they may be related to sex hormone-mediated unknown rapid non-genomic action that cannot be currently explained by their genomic action via nuclear receptors. Progesterone affects cell proliferation and survival via non-genomic effects. In this process, membrane progesterone receptors (mPRα, mPRβ, mPRγ, mPRδ, and mPRε) were identified as putative G protein-coupled receptors (GPCRs) for progesterone. However, the structure, intracellular signaling, and physiological functions of these progesterone receptors are still unclear. Here, we identify a molecular mechanism by which progesterone promotes neurite outgrowth through mPRβ (Paqr8) activation. Mouse mPRβ mRNA was specifically expressed in the central nervous system. It has an incomplete GPCR topology, presenting 6 transmembrane domains and did not exhibit typical GPCR signaling. Progesterone-dependent neurite outgrowth was exhibited by the promotion of ERK phosphorylation via mPRβ, but not via other progesterone receptors such as progesterone membrane receptor 1 (PGRMC-1) and nuclear progesterone receptor in nerve growth factor-induced neuronal PC12 cells. These findings provide new insights of regarding the non-genomic action of progesterone in the central nervous system.

Experience-dependent homeostasis of 'noise' at inhibitory synapses preserves information coding in adult visual cortex.

Synapses are intrinsically 'noisy' in that neurotransmitter is occasionally released in the absence of an action potential. At inhibitory synapses, the frequency of action potential-independent release is orders of magnitude higher than that at excitatory synapses raising speculations that it may serve a function. Here we report that the frequency of action potential-independent inhibitory synaptic 'noise' (i.e. miniature inhibitory postsynaptic currents, mIPSCs) is highly regulated by sensory experience in visual cortex. Importantly, regulation of mIPSC frequency is so far the predominant form of functional plasticity at inhibitory synapses in adults during the refractory period for plasticity and is a locus of rapid non-genomic actions of oestrogen. Models predict that regulating the frequency of mIPSCs, together with the previously characterized synaptic scaling of miniature excitatory PSCs, allows homeostatic maintenance of both the mean and variance of inputs to a neuron, a necessary feature of probabilistic population codes. Furthermore, mIPSC frequency regulation allows preservation of the temporal profile of neural responses while homeostatically regulating the overall firing rate. Our results suggest that the control of inhibitory 'noise' allows adaptive maintenance of adult cortical function in tune with the sensory environment.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.

The Non-Genomic Actions of Vitamin D

Since its discovery in 1920, a great deal of effort has gone into investigating the physiological actions of vitamin D and the impact its deficiency has on human health. Despite this intense interest, there is still disagreement on what constitutes the lower boundary of adequacy and on the Recommended Dietary Allowance. There has also been a major push to elucidate the biochemistry of vitamin D, its metabolic pathways and the mechanisms that mediate its action. Originally thought to act by altering the expression of target genes, it was realized in the mid-1980s that some of the actions of vitamin D were too rapid to be accounted for by changes at the genomic level. These rapid non-genomic actions have attracted as much interest as the genomic actions and they have spawned additional questions in an already busy field. This mini-review attempts to summarise the in vitro and in vivo work that has been conducted to characterise the rapid non-genomic actions, the mechanisms that give rise to these properties and the roles that these play in the overall action of vitamin D at the cellular level. Understanding the effects of vitamin D at the cellular level should enable the design of elegant human studies to extract the full potential of vitamin D to benefit human health.

Direct effects of estrogens on cholinergic primary neurons from the human fetal nucleus basalis of Meynert

Epidemiological studies have indicated that Alzheimer’s disease (AD) is more common in females and that post-menopausal women are at increased risk than their male counterpart, thus suggesting that estrogens could play a protective role to counteract neurodegenerative processes (1). However, the mechanisms underlying this association remain to be clarified. Since the nucleus basalis of Meynert (nbM) is the major source of cholinergic innervation selectively vulnerable to degeneration in AD, our study is aimed at investigating the effects of estrogens on human cholinergic primary neurons (hfCNs) isolated from the nbM of 12-week old fetuses. The primary culture obtained was immunophenotyped with flow cytometry and resulted almost totally positive (97±2 %) for the neuronal marker MAP2 and for the choline acetyltransferase (ChAT). We demonstrated that hfCNs express receptors for hormones of the reproductive axis (ERs, LHR, GnRHR). In particular, besides to classical estrogen receptors (ERa and ERb), hfCNs express the transmembrane receptor GPR30, which is known to mediate rapid non-genomic estrogen actions. Increasing concentrations of 17-β estradiol (E2, 0.1-100 nM) determined a dose-dependent significant increase in cell number after 24h exposure, which was antagonized by tamoxifen treatment. In addition, E2 exposure determined a significant increase in ChAT expression, thus indicating a direct positive effect of E2 on cholinergic phenotype. Given that substantial evidence now indicates that estrogens exert an anti-inflammatory activity even in the central nervous system (2), we exposed hfCN cells to the proinflammatory cytokine TNFα. E2 treatment (1nM) was able to significantly counteract the TNFα-induced nuclear NF-kB p65 translocation. Interestingly, this effect was mimicked by G1, a GPR30 agonist, and abolished by pretreating cells with the GPR30 antagonist G15, but not by tamoxifen, which usually antagonizes classical ERs. Overall, our results indicate that estrogens exert direct neuroprotective mechanisms on hfCNs through the activation of either classical (trophic) and non-classical (anti-inflammatory) receptors.

Involvement of nucleotide diphosphate kinase 2 in the reopening of the sensitive period of filial imprinting of domestic chicks (Gallus gallus domesticus)

Filial imprinting is a behavior characterized by the sensitive or critical period restricted to the first few days after hatching. Once the sensitive period is closed, it is widely believed that chicks can never be imprinted under natural conditions. Previously, we showed that the exogenous injection of T3 reopened the sensitive period which was already closed. That study suggested that T3 functioned by way of a rapid non-genomic action; however, the molecular mechanism of how T3 reopens the sensitive period remains unknown. Here, we show that the phosphorylation level of nucleotide diphosphate kinase 2 (NDPK2) was upregulated following T3 injection. Pharmacological deprivation of the kinase activity of NDPK hampered the molecular process prerequisite for the reopening of the sensitive period of filial imprinting. Moreover, it is shown that the kinase activity of NDPK2 participates in the priming process by T3 signaling which endows the potential for learning. Our data indicate that NDPK2 plays a crucial role downstream of T3 action and that its phosphorylation is involved in the non-genomic signaling during imprinting.

Hypothalamic Nuclear Glucocorticoid Receptors: Acute Stress and Rapid Actions.

Stress, be it physical or psychological, causes the activation of a neuroendocrine cascade that involves both central and peripheral mechanisms. In the simplest terms, central release of CRH from the paraventricular nucleus of thehypothalamus (PVN)andsubsequent releaseofACTH from the pituitary result in the peripheral release of glucocorticoids (cortisol in primates and corticosterone in many rodent species) from the adrenal gland (1). Glucocorticoids then act via negative feedback both centrally and peripherally through the glucocorticoid receptor (GR) to inhibit the further release of CRH from the PVN and ACTH from the pituitary (2). This process is a delicate balance that helps restore homeostasis, but perturbation of these responses can lead to neurobehavioral and physiological dysfunctions, including mood disorders and obesity (3–5). Hence, understanding the basic mechanisms that mediate this neuroendocrine loop has broad implications for both health and disease. Two companion papers in this issue by Solomon et al (6) and Nahar et al (7) have helped to further reveal the mechanisms through which glucocorticoids influence hypothalamic-pituitary-adrenal (HPA) function. Both reports use a powerful mouse model in which Sim1-cre recombinase transgenic mice are bred with homozygous floxed GR mice. Sim1 is a transcription factor specifically expressed in the PVN, supraoptic nucleus, and periventricular nucleus (8) and is responsible for the proper maturation of neurosecretory cells in the PVN (9). As Solomon et al report, theoffspring fromthis cross showsignificantly reduced GR levels in the PVN while leaving GR levels intact in the pituitary and other brain regions important in glucocorticoid-dependent negative feedback (6), thus resulting in a relatively anatomically restricted GR reduction. Using these PVN GR knockdown (KD) mice, Solomon et al (6) find sex-specific and stressor-dependent effects on HPA reactivity. In particular, they show GR KD mice respond to a brief 30-minute session of restraint stress with significantly increased and prolonged ACTH and corticosterone responses compared with their littermate controls, suggesting reduced negative feedback on the HPA axis (6). Notably, however, these effects of GR KD were observed only in males because female GR KD mice show reduced restraint-induced ACTH and no differences in stress-induced corticosterone responsiveness. In response to chronic variable stress, neither male nor female GR KD mice show any differences in HPA reactivity. Hence, the authors conclude that there are significant sex differences in the role that PVN GR plays in response to acute stress and that changes in HPA reactivity after chronic stress in male and female mice are independent of GR in the PVN (6). Complimenting this line of research, the report by Nahar et al (7) investigated rapid nongenomic actions of glucocorticoids in modulating excitatory and inhibitory transmission in the mouse hypothalamus. They show that hypothalamic magnocellular neurons respond to dexamethasone (DEX), a synthetic glucocorticoid, with a rapid suppression of excitatory postsynaptic inputs (ie, glutamatergic synapses). The authors further demonstrate that this effect of DEX is mediated by postsynaptic membrane associated receptors and G protein signaling (7), similar to their seminal work in rats (10–12). The authors also show that DEX leads to a rapid nitric oxide-dependent increase in inhibitory postsynaptic inputs [ie, -aminobutyric acid

Hypothalamic-Pituitary--Adrenal Axis-Feedback Control.

The hypothalamo-pituitary-adrenal axis (HPA) is responsible for stimulation of adrenal corticosteroids in response to stress. Negative feedback control by corticosteroids limits pituitary secretion of corticotropin, ACTH, and hypothalamic secretion of corticotropin-releasing hormone, CRH, and vasopressin, AVP, resulting in regulation of both basal and stress-induced ACTH secretion. The negative feedback effect of corticosteroids occurs by action of corticosteroids at mineralocorticoid receptors (MR) and/or glucocorticoid receptors (GRs) located in multiple sites in the brain and in the pituitary. The mechanisms of negative feedback vary according to the receptor type and location within the brain-hypothalmo-pituitary axis. A very rapid nongenomic action has been demonstrated for GR action on CRH neurons in the hypothalamus, and somewhat slower nongenomic effects are observed in the pituitary or other brain sites mediated by GR and/or MR. Corticosteroids also have genomic actions, including repression of the pro-opiomelanocortin (POMC) gene in the pituitary and CRH and AVP genes in the hypothalamus. The rapid effect inhibits stimulated secretion, but requires a rapidly rising corticosteroid concentration. The more delayed inhibitory effect on stimulated secretion is dependent on the intensity of the stimulus and the magnitude of the corticosteroid feedback signal, but also the neuroanatomical pathways responsible for activating the HPA. The pathways for activation of some stressors may partially bypass hypothalamic feedback sites at the CRH neuron, whereas others may not involve forebrain sites; therefore, some physiological stressors may override or bypass negative feedback, and other psychological stressors may facilitate responses to subsequent stress.

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex.

The hippocampus provided the gateway into much of what we have learned about stress and brain structural and functional plasticity, and this initial focus has expanded to other interconnected brain regions, such as the amygdala and prefrontal cortex. Starting with the discovery of adrenal steroid, and later, estrogen receptors in the hippocampal formation, and subsequent discovery of dendritic and spine synapse remodeling and neurogenesis in the dentate gyrus, mechanistic studies have revealed both genomic and rapid non-genomic actions of circulating steroid hormones in the brain. Many of these actions occur epigenetically and result in ever-changing patterns of gene expression, in which there are important sex differences that need further exploration. Moreover, glucocorticoid and estrogen actions occur synergistically with an increasing number of cellular mediators that help determine the qualitative nature of the response. The hippocampus has also been a gateway to understanding lasting epigenetic effects of early-life experiences. These findings in animal models have resulted in translation to the human brain and have helped change thinking about the nature of brain malfunction in psychiatric disorders and during aging, as well as the mechanisms of the effects of early-life adversity on the brain and the body.

Effects of estrogens and estrogenic disrupting compounds on fish mineralized tissues.

Estrogens play well-recognized roles in reproduction across vertebrates, but also intervene in a wide range of other physiological processes, including mineral homeostasis. Classical actions are triggered when estrogens bind and activate intracellular estrogen receptors (ERs), regulating the transcription of responsive genes, but rapid non-genomic actions initiated by binding to plasma membrane receptors were recently described. A wide range of structurally diverse compounds from natural and anthropogenic sources have been shown to interact with and disrupt the normal functions of the estrogen system, and fish are particularly vulnerable to endocrine disruption, as these compounds are frequently discharged or run-off into waterways. The effect of estrogen disruptors in fish has mainly been assessed in relation to reproductive endpoints, and relatively little attention has been given to other disruptive actions. This review will overview the actions of estrogens in fish, including ER isoforms, their expression, structure and mechanisms of action. The estrogen functions will be considered in relation to mineral homeostasis and actions on mineralized tissues. The impact of estrogenic endocrine disrupting compounds on fish mineralized tissues will be reviewed, and the potential adverse outcomes of exposure to such compounds will be discussed. Current lacunae in knowledge are highlighted along with future research priorities.

Stress and corticosterone increase the readily releasable pool of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex

Stress and glucocorticoids alter glutamatergic transmission, and the outcome of stress may range from plasticity enhancing effects to noxious, maladaptive changes. We have previously demonstrated that acute stress rapidly increases glutamate release in prefrontal and frontal cortex via glucocorticoid receptor and accumulation of presynaptic SNARE complex. Here we compared the ex vivo effects of acute stress on glutamate release with those of in vitro application of corticosterone, to analyze whether acute effect of stress on glutamatergic transmission is mediated by local synaptic action of corticosterone. We found that acute stress increases both the readily releasable pool (RRP) of vesicles and depolarization-evoked glutamate release, while application in vitro of corticosterone rapidly increases the RRP, an effect dependent on synaptic receptors for the hormone, but does not induce glutamate release for up to 20 min. These findings indicate that corticosterone mediates the enhancement of glutamate release induced by acute stress, and the rapid non-genomic action of the hormone is necessary but not sufficient for this effect.

The many faces of estrogen signaling.

Estrogens have long been known as important regulators of the female reproductive functions; however, our understanding of the role estrogens play in the human body has changed significantly over the past years. It is now commonly accepted that estrogens and androgens have important functions in both female and male physiology and pathology. This is in part due to the local synthesis and action of estrogens that broadens the role of estrogen signaling beyond that of the endocrine system. Furthermore, there are several different mechanisms through which the three estrogen receptors (ERs), ERα, ERβ and G protein-coupled estrogen receptor 1 (GPER1) are able to regulate target gene transcription. ERα and ERβ are mostly associated with the direct and indirect genomic signaling pathways that result in target gene expression. Membrane-bound GPER1 is on the other hand responsible for the rapid non-genomic actions of estrogens that activate various protein-kinase cascades. Estrogen signaling is also tightly connected with another important regulatory entity, i.e. epigenetic mechanisms. Posttranslational histone modifications, microRNAs (miRNAs) and DNA methylation have been shown to influence gene expression of ERs as well as being regulated by estrogen signaling. Moreover, several coregulators of estrogen signaling also exhibit chromatin-modifying activities further underlining the importance of epigenetic mechanisms in estrogen signaling. This review wishes to highlight the newer aspects of estrogen signaling that exceed its classical endocrine regulatory role, especially emphasizing its tight intertwinement with epigenetic mechanisms.

Differentiation between genomic and non-genomic feedback controls yields an HPA axis model featuring Hypercortisolism as an irreversible bistable switch

BackgroundThe hypothalamic-pituitary-adrenal axis (HPA axis) is a major part of the neuroendocrine system responsible for the regulation of the response to physical or mental stress and for the control of the synthesis of the stress hormone cortisol. Dysfunctions of the HPA axis characterized by either low (hypocortisolism) or increased (hypercortisolism) cortisol levels are implicated in various pathological conditions. Their understanding and therapeutic correction may be supported by mathematical modeling and simulation of the HPA axis.MethodsMass action and Michaelis Menten enzyme kinetics were used to provide a mechanistic description of the feedback mechanisms within the pituitary gland cells by which cortisol inhibits its own production. A separation of the nucleus from the cytoplasm by compartments enabled a differentiation between slow genomic and fast non-genomic processes. The model in parts was trained against time resolved ACTH stress response data from an in vitro cell culture of murine AtT-20 pituitary tumor cells and analyzed by bifurcation discovery tools.ResultsA recently found pituitary gland cell membrane receptor that mediates rapid non-genomic actions of glucocorticoids has been incorporated into our model of the HPA axis. As a consequence of the distinction between genomic and non-genomic feedback processes our model possesses an extended dynamic repertoire in comparison to existing HPA models. In particular, our model exhibits limit cycle oscillations and bistable behavior associated to hypocortisolism but also features a (second) bistable switch which captures irreversible transitions in hypercortisolism to elevated cortisol levels.ConclusionsModel predictive control and inverse bifurcation analysis have been previously applied in the simulation-based design of therapeutic strategies for the correction of hypocortisolism. Given the HPA model extension presented in this paper, these techniques may also be used in the study of hypercortisolism. As an example, we show how sparsity enforcing penalization may suggest network interventions that allow the return from elevated cortisol levels back to nominal ones.

Estrogen receptor-mediated transcription involves the activation of multiple kinase pathways in neuroblastoma cells

While many physiological effects of estrogens (E) are due to regulation of gene transcription by liganded estrogen receptors (ERs), several effects are also mediated, at least in part, by rapid non-genomic actions of E. Though the relative importance of rapid versus genomic effects in the central nervous system is controversial, we showed previously that membrane-limited effects of E, initiated by an estradiol bovine serum albumin conjugate (E2-BSA), could potentiate transcriptional effects of 17β-estradiol from an estrogen response element (ERE)-reporter in neuroblastoma cells. Here, using specific inhibitors and activators in a pharmacological approach, we show that activation of phosphatidylinositol-3-phosphate kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways, dependent on a Gαq coupled receptor signaling are important in this transcriptional potentiation. We further demonstrate, using ERα phospho-deficient mutants, that E2-BSA mediated phosphorylation of ERα is one mechanism to potentiate transcription from an ERE reporter construct. This study provides a possible mechanism by which signaling from the membrane is coupled to transcription in the nucleus, providing an integrated view of hormone signaling in the brain.

THU0127 Functional activity of membrane-bound glucocorticoid receptors

BackgroundGlucocorticoids are among the most commonly used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic diseases. They exert their anti-inflammatory and immunosuppressive effects primarily via the cytosolic glucocorticoid receptor...

Ligand-bound Thyroid Hormone Receptor Contributes to Reprogramming of Pancreatic Acinar Cells into Insulin-producing Cells

One goal of diabetic regenerative medicine is to instructively convert mature pancreatic exocrine cells into insulin-producing cells. We recently reported that ligand-bound thyroid hormone receptor α (TRα) plays a critical role in expansion of the β-cell mass during postnatal development. Here, we used an adenovirus vector that expresses TRα driven by the amylase 2 promoter (AdAmy2TRα) to induce the reprogramming of pancreatic acinar cells into insulin-producing cells. Treatment with l-3,5,3-triiodothyronine increases the association of TRα with the p85α subunit of phosphatidylinositol 3-kinase (PI3K), leading to the phosphorylation and activation of Akt and the expression of Pdx1, Ngn3, and MafA in purified acinar cells. Analyses performed with the lectin-associated cell lineage tracing system and the Cre/loxP-based direct cell lineage tracing system indicate that newly synthesized insulin-producing cells originate from elastase-expressing pancreatic acinar cells. Insulin-containing secretory granules were identified in these cells by electron microscopy. The inhibition of p85α expression by siRNA or the inhibition of PI3K by LY294002 prevents the expression of Pdx1, Ngn3, and MafA and the reprogramming to insulin-producing cells. In immunodeficient mice with streptozotocin-induced hyperglycemia, treatment with AdAmy2TRα leads to the reprogramming of pancreatic acinar cells to insulin-producing cells in vivo. Our findings suggest that ligand-bound TRα plays a critical role in β-cell regeneration during postnatal development via activation of PI3K signaling.

The role of progesterone in implantation and trophoblast invasion

With its genomic and non-genomic actions, progesterone plays a role in preparing the endometrium for implantation and also in regulating trophoblast invasion and migration. The genomic actions of progesterone are mediated by the classical nuclear progesterone receptors, PR-A and PR-B. In addition to their genomic actions, nuclear progesterone receptors may also trigger rapid cytoplasmic signalling events. Membrane-bound progesterone receptors have been implicated in the rapid non-genomic actions of progesterone. Both genomic and extra-nuclear actions of progesterone are crucial for adequate decidualisation and implantation. Progesterone plays a role in establishing uterine receptivity by blocking the proliferative effect of oestrogen, by inducing genes that allow the endometrium to permit embryo attachment, and also acts as a negative regulator of trophoblast invasion by controlling matrix metalloproteinase (MMP) activity.

Neurotrophic effects of neudesin in the central nervous system

Neudesin (neuron-derived neurotrophic factor; NENF) was identified as a neurotrophic factor that is involved in neuronal differentiation and survival. It is abundantly expressed in the central nervous system, and its neurotrophic activity is exerted via the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. Neudesin is also an anorexigenic factor that suppresses food intake in the hypothalamus. It is a member of the membrane-associated progesterone receptor (MAPR) family and shares key structural motifs with the cytochrome b5-like heme/steroid-binding domain. Progesterone receptor membrane component 1 (PGRMC1), the first to be discovered among the MAPR family, binds progesterone to induce “rapid non-genomic effects” in biological responses that are unrelated to the nuclear progesterone receptors (PRs). Hence, neudesin may also be involved in the rapid non-genomic actions of progesterone. In this review, we summarize the identification, structure, and activity of neudesin in the central nervous system, and present an essential overview of the current understanding of its physiological roles and the prospect of elucidating its non-genomic progesterone effects.

Conservative Nature of Oestradiol Signalling Pathways in the Brain Lobes of Octopus vulgaris Involved in Reproduction, Learning and Motor Coordination

Oestradiol plays crucial roles in the mammalian brain by modulating reproductive behaviour, neural plasticity and pain perception. The cephalopod Octopus vulgaris is considered, along with its relatives, to be the most behaviourally advanced invertebrate, although the neurophysiological basis of its behaviours, including pain perception, remain largely unknown. In the present study, using a combination of molecular and imaging techniques, we found that oestradiol up-regulated O.vulgaris gonadotrophin-releasing hormone (Oct-GnRH) and O.vulgaris oestrogen receptor (Oct-ER) mRNA levels in the olfactory lobes; in turn, Oct-ER mRNA was regulated by NMDA in lobes involved in learning and motor coordination. Fluorescence resonance energy transfer analysis revealed that oestradiol binds Oct-ER causing conformational modifications and nuclear translocation consistent with the classical genomic mechanism of the oestrogen receptor. Moreover, oestradiol triggered a calcium influx and cyclic AMP response element binding protein phosphorylation via membrane receptors, providing evidence for a rapid nongenomic action of oestradiol in O.vulgaris. In the present study, we demonstrate, for the first time, the physiological role of oestradiol in the brain lobes of O.vulgaris involved in reproduction, learning and motor coordination.