Emerging insights into the structure and function of ionotropic glutamate delta receptors.

Glutamate delta-1 (GluD1) and delta-2 (GluD2) receptors belong to the orphan GluD subfamily of ionotropic glutamate receptors (iGluRs). GluDs were classified as ionotropic glutamate receptors based on their sequence similarity. Two decades after these GluDs were first cloned they are still considered "orphan" due to a lack of knowledge of the endogenous ligands that can activate them. Nevertheless, they are crucial for synapse formation, maturation and maintenance of CNS functions, and are implicated in multiple neuronal disorders, including schizophrenia, autism spectrum disorder and depressive disorders. Over the last decade significant discoveries have been made, include role of GluD receptors in mediating trans-synaptic interactions and their unique non-swapped architecture, which is distinct from other ionotropic glutamate receptors. Also, the prospect of GluD ionotropic activity being regulated by direct interaction with metabotropic glutamate receptors is exciting. These discoveries will likely drive the field in the future, providing direction to GluD research. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.

Altered estradiol-dependent cellular Ca2+ homeostasis and endoplasmic reticulum stress response in Premenstrual Dysphoric Disorder.

Premenstrual Dysphoric Disorder (PMDD) is characterized by debilitating mood symptoms in the luteal phase of the menstrual cycle. Prior studies of affected women have implicated a differential response to ovarian steroids. However, the molecular basis of these patients' differential response to hormone remains poorly understood. We performed transcriptomic analyses of lymphoblastoid cell lines (LCLs) derived from women with PMDD and asymptomatic controls cultured under untreated (steroid-free), estradiol-treated (E2), and progesterone-treated (P4) conditions. Weighted gene correlation network analysis (WGCNA) of transcriptomes identified four gene modules with significant diagnosis x hormone interactions, including one enriched for neuronal functions. Next, in a gene-level analysis comparing transcriptional response to hormone across diagnoses, a generalized linear model identified 1522 genes differentially responsive to E2 (E2-DRGs). Among the top 10 E2-DRGs was a physically interacting network (NUCB1, DST, GCC2, GOLGB1) involved in endoplasmic reticulum (ER)-Golgi function. qRT-PCR validation reproduced a diagnosis x E2 interaction (F(1,24)=7.01, p = 0.014) for NUCB1, a regulator of cellular Ca2+ and ER stress. Finally, we used a thapsigargin (Tg) challenge assay to test whether E2 induces differences in Ca2+ homeostasis and ER stress response in PMDD. PMDD LCLs had a 1.36-fold decrease in Tg-induced XBP1 splicing response compared to controls, and a 1.62-fold decreased response (p = 0.005), with a diagnosis x treatment interaction (F(3,33)=3.51, p = 0.026) in the E2-exposed condition. Altered hormone-dependent in cellular Ca2+ dynamics and ER stress may contribute to the pathophysiology of PMDD.

Epigenetic intersection of BDNF Val66Met genotype with premenstrual dysphoric disorder transcriptome in a cross-species model of estradiol add-back.

Premenstrual dysphoric disorder (PMDD) affects over 5% of women, with symptoms similar to anxiety and major depression, and is associated with differential sensitivity to circulating ovarian hormones. Little is known about the genetic and epigenetic factors that increase the risk to develop PMDD. We report that 17ß-estradiol (E2) affects the behavior and the epigenome in a mouse model carrying a single-nucleotide polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met), in a way that recapitulates the hallmarks of PMDD. Ovariectomized mice heterozygous for the BDNF Met allele (Het-Met) and their matched wild-type (WT) mice were administered estradiol or vehicle in drinking water for 6 weeks. Using the open field and the splash test, we show that E2 add-back induces anxiety-like and depression-like behavior in Het-Met mice, but not in WT mice. RNA-seq of the ventral hippocampus (vHpc) highlights that E2-dependent gene expression is markedly different between WT mice and Het-Met mice. Through a comparative whole-genome RNA-seq analysis between mouse vHpc and lymphoblastoid cell line cultures from control women and women with PMDD, we discovered common epigenetic biomarkers that transcend species and cell types. Those genes include epigenetic modifiers of the ESC/E(Z) complex, an effector of response to ovarian steroids. Although the BDNF Met genotype intersects the behavioral and transcriptional traits of women with PMDD, we suggest that these similarities speak to the epigenetic factors by which ovarian steroids produce negative behavioral effects.

Paracrine role of macrophage produced-nitric oxide (NO) in Leydig cell steroidogenesis in a teleost, Clarias batrachus: Impact of gonadotropin, growth hormone and insulin on NO production by testicular macrophages.

The present in vitro study for the first time demonstrates the role of extragonadal hormones in regulation of NO production by testicular macrophages in vertebrates and paracrine role of NO in Leydig cell steroidogenesis in fishes. N-nitro L-arginine methyl ester (L-NAME - a NOS inhibitor) treatment substantially reduced NO production by testicular macrophages suggesting that testicular macrophages are one of the sources of testicular NO in the catfish, Clarias batrachus. Significant decline in NO production was also recorded following treatment of macrophages with the gonadotropin (GtH), growth hormone (GH) and insulin indicating that macrophage-produced NO is under endocrine inhibitory control. Treatment of Leydig cells with sodium nitroprusside (SNP) decreased testosterone (T) production. SNP treatment also remarkably suppressed the GtH, GH and insulin-stimulated T production by Leydig cells indicating that Leydig cell steroidogenesis is sensitive to exogenous NO. Further, effect of conditioned medium of testicular macrophages incubated with medium alone (non-treated TMCM) or GtH (GtH-treated TMCM) or GH (GH-treated TMCM) or insulin (insulin-treated TMCM) were also observed on Leydig cell T production. Non-treated TMCM as well as hormone-treated TMCM stimulated T production by Leydig cells; hormone-treated TMCM were more effective in stimulating T production than non-treated TMCM and/or hormones alone. These experiments altogether suggest that testicular macrophage secrete some factors, which influence Leydig cell steroidogenic activity through paracrine mechanism, and these paracrine secretions are under the endocrine control. Decline in NO in hormone-treated TMCM might also be one of the reasons for more stimulation in T production than that of hormones alone.