During evolution, mammals have developed remarkably similar molecular mechanisms to respond to external challenges and maintain survival. Critical regulators of these mechanisms are the family of ...‘stress’‐peptides that consists of the corticotropin‐releasing hormone (CRH) and urocortins (Ucns). These neuropeptides ‘fine‐tune’ integration of an intricate series of physiological responses involving the autonomic, endocrine, immune, cardiovascular and reproductive systems, which induce a spectrum of behavioural and homeostatic changes. CRH and Ucns exert their actions by activating two types of CRH receptors (CRH‐R), CRH‐R1 and CRH‐R2, which belong to the class‐B1 family of GPCRs. The CRH‐Rs exhibit signalling promiscuity facilitated by their ability to couple to multiple G‐proteins and regulate diverse intracellular networks that involve intracellular effectors such as cAMP and an array of PKs in an agonist and tissue‐specific manner, a property that allows them to exert unique roles in the integration of homeostatic mechanisms. We only now begin to unravel the plethora of CRH‐R biological actions and the transcriptional and post‐translational mechanisms such as alternative mRNA splicing or phosphorylation‐mediated desensitization developed to tightly control CRH‐Rs biological activity and regulate their physiological actions. This review summarizes the current understanding of CRH‐R signalling complexity and regulatory mechanisms that underpin cellular responses to CRH and Ucns.
LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein‐Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue‐1
G-protein coupled receptors (GPCRs) have long been at the center of investigations of the neurobiology of depression and mood disorders. Different facets of GPCR signalling pathways, including those ...controlling monoaminergic and neuropeptidergic hormonal systems are believed to be dysregulated in major depressive and bipolar disorders. Although these receptors are key molecular targets for a variety of therapeutic agents and continue to be the focus of intense pharmaceutical development, the molecular mechanisms activated by these GPCRs and underpin the pathological basis of mood disorders remain poorly understood. This review will discuss some of the emerging regulatory mechanisms of GPCR signaling in the central nervous system (CNS) involving protein-protein interactions, downstream effectors and cross-talk with other signaling molecules and their potential involvement in the neurobiology of psychiatric disease.
•GPCRs are involved in the pathogenesis of depression and mood disorders.•Oligomerization of GPCRs is now linked with aberrant signaling involved in development of depression.•Regulators of GPCR signaling such as RGS, GRK and β-arrestin represent potential therapeutic targets for mood disorders.•Tissue specific changes in regulators of GPCR signaling can be captured by parallel changes in circulating blood cells.
BackgroundPre-eclampsia remains a leading cause of maternal and foetal mortality with a poorly understood pathophysiology. It can lead to a range of clinical presentations, but proteinuria and ...hypertension are key components of the diagnosis. These signs arise due to disordered placental implantation due to poor trophoblastic invasion, resulting in placental oxidative stress due to hypoxia. Oxidative stress triggers the release of syncytiotrophoblast microvesicles (STMBs), of which placenta-derived exosomes may be a key component. The high specificity of exosomes for their cell of origin makes them ideal candidates as diagnostic biomarkers. We are particularly interested in the miRNAs (microRNAs) contained within these exosomes, as they may give us an insight into the genomic regulation within the pre-eclamptic placenta that leads to the disease state. The development of workflows for miRNA quantitation may enable us to identify novel biomarkers.MethodsWe extracted exosomes and purified total RNA from 23 serum samples using the Norgen Plasma/Serum Exosome Purification and RNA Isolation Midi Kit. We then used the bioanalyser to determine the concentration and quality of the RNA obtained. It uses rapid electrophoresis, requires minimal sample sizes, and can assess the quality of genetic material as small as 25 bases.ResultsWe have successfully isolated RNA from these samples; however, the concentration of the total RNA was too low for downstream molecular analysis. We did gain insight into how to optimise and develop the workflow so that, with each attempt, the yield increased. Our greatest concentrations were obtained by combining serum samples from multiple patients, demonstrating that we needed a higher volume to optimise the yield. Future studies should aim to obtain samples specifically for use in this research so that we can process a larger volume of serum.ConclusionsWe have also noted that there is a positive correlation between the overall concentration of total RNA and a high sFlt-1/PlGF ratio. Preliminary analysis from Illumina identified with a high degree of confidence the presence of three miRNAs, namely, mir-498(46), mir-122(1), and mir-134(41). Further work is necessary to validate these findings and should focus on the possible future role of these miRNAs as biomarkers for the early diagnosis of pre-eclampsia.
The CRH receptor (CRH-R) is a member of the secretin family of G protein-coupled receptors. Wide expression of CRH-Rs in the central nervous system and periphery ensures that their cognate agonists, ...the family of CRH-like peptides, are capable of exerting a wide spectrum of actions that underpin their critical role in integrating the stress response and coordinating the activity of fundamental physiological functions, such as the regulation of the cardiovascular system, energy balance, and homeostasis. Two types of mammal CRH-R exist, CRH-R1 and CRH-R2, each with unique splicing patterns and remarkably distinct pharmacological properties, but similar signaling properties, probably reflecting their distinct and sometimes contrasting biological functions. The regulation of CRH-R expression and activity is not fully elucidated, and we only now begin to fully understand the impact on mammalian pathophysiology. The focus of this review is the current and evolving understanding of the molecular mechanisms controlling CRH-R biological activity and functional flexibility. This shows notable tissue-specific characteristics, highlighted by their ability to couple to distinct G proteins and activate tissue-specific signaling cascades. The type of activating agonist, receptor, and target cell appears to play a major role in determining the overall signaling and biological responses in health and disease.
Early life is a period of considerable plasticity and vulnerability and insults during that period can disrupt the homeostatic equilibrium of the developing organism, resulting in adverse ...developmental programming and enhanced susceptibility to disease. Fetal exposure to prenatal stress can impede optimum brain development and deranged mother's hypothalamic-pituitary-adrenal axis (HPA axis) stress responses can alter the neurodevelopmental trajectories of the offspring. Corticotropin-releasing hormone (CRH) and glucocorticoids, regulate fetal neurogenesis and while CRH exerts neuroprotective actions, increased levels of stress hormones have been associated with fetal brain structural alterations such as reduced cortical volume, impoverishment of neuronal density in the limbic brain areas and alterations in neuronal circuitry, synaptic plasticity, neurotransmission and G-protein coupled receptor (GPCR) signalling. Emerging evidence highlight the role of epigenetic changes in fetal brain programming, as stress-induced methylation of genes encoding molecules that are implicated in HPA axis and major neurodevelopmental processes. These serve as molecular memories and have been associated with long term modifications of the offspring's stress regulatory system and increased susceptibility to psychosomatic disorders later in life. This review summarises our current understanding on the roles of CRH and other mediators of stress responses on fetal neurodevelopment.
Abstract Women with postnatal depression (PND) appear to have abnormal hypothalamic pituitary adrenal (HPA) axis responses to stress, which might involve a genetic variability component. We ...investigated association of genetic variants in the glucocorticoid receptor (GR, NR3C1) and corticotropin releasing hormone receptor 1 (CRHR1) genes with increased risk for PND. Two hundred pregnant women were recruited prospectively and PND risk was assessed by the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy and again 2–8 weeks post-natally (CW-GAPND study). The BclI and ER22/23EK single nucleotide polymorphisms (SNPs) of the GR and the haplotype-tagged rs1876828, rs242939 and rs242941 SNPs of the CRHR1 associated with genetic risk to depressive disorders were genotyped. A cut-off score of 10 was used to detect increased risk of PND. Association analysis was carried out in 140 patients that completed the study protocol. The BclI and rs242939 SNPs were over-represented in women with postnatal EPDS score ≥10 with significant allele association ( p = 0.011 and <0.001, respectively) and risk ratios of 2.9 (95% CI: 1.2–6.9) for BclI, 4.9 (2–12) for rs242939 and 5.48 (2.13–14.10) for both. The rs242939 SNP was also associated with increased EPDS values during pregnancy. Moreover, the G-G-T haplotype of the CRHR1 was significantly over-represented in patients with high EPDS scores, with risk ratio of 3.22 (95% CI: 1.91–5.42). This is the first evidence that specific SNPs of genes involved in ‘stress’ responses might contribute in the genetics of high-risk for depression during pregnancy and postpartum.
Perinatal depression involves interplay between individual chronic and acute disease burdens, biological and psychosocial environmental and behavioural factors. Here we explored the predictive ...potential of specific psycho-socio-demographic characteristics for antenatal and postpartum depression symptoms and contribution to severity scores on the Edinburgh Postnatal Depression Scale (EPDS) screening tool. We determined depression risk trajectories in 480 women that prospectively completed the EPDS during pregnancy (TP1) and postpartum (TP2). Multinomial logistic and penalised linear regression investigated covariates associated with increased antenatal and postpartum EPDS scores contributing to the average or the difference of paired scores across time points. History of anxiety was identified as the strongest contribution to antenatal EPDS scores followed by the social status, whereas a history of depression, postpartum depression (PPD) and family history of PPD exhibited the strongest association with postpartum EPDS. These covariates were the strongest differentiating factors that increased the spread between antenatal and postpartum EPDS scores. Available covariates appeared better suited to predict EPDS scores antenatally than postpartum. As women move from the antenatal to the postpartum period, socio-demographic and lifestyle risk factors appear to play a smaller role in risk, and a personal and family history of depression and PPD become increasingly important.
Familial hypercholesterolemia (FH) is a common genetic cause of premature cardiovascular disease (CVD). The reported prevalence rates for both heterozygous FH (HeFH) and homozygous FH (HoFH) vary ...significantly, and this can be attributed, at least in part, to the variable diagnostic criteria used across different populations. Due to lack of consistent data, new global registries and unified guidelines are being formed, which are expected to advance current knowledge and improve the care of FH patients. This review presents a comprehensive overview of the pathophysiology, epidemiology, manifestations, and pharmacological treatment of FH, whilst summarizing the up-to-date relevant recommendations and guidelines. Ongoing research in FH seems promising and novel therapies are expected to be introduced in clinical practice in order to compliment or even substitute current treatment options, aiming for better lipid-lowering effects, fewer side effects, and improved clinical outcomes.
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