Molecular mechanism of action of pharmacoperone rescue of misrouted GPCR mutants: the GnRH receptor.

The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs that rescue misfolded and misrouted protein mutants and restore them to function. This technique forms the basis of a therapeutic approach of rescuing mutants associated with human disease and restoring them to function. The present study relies on computational modeling, followed by site-directed mutagenesis, assessment of ligand binding, effector activation, and confocal microscopy.

Hypothalamic expression of Eap1 is not directly controlled by ovarian steroids.

A gene termed EAP1 (enhanced at puberty 1) was recently identified as a transcriptional regulator of female neuroendocrine reproductive function. We have now used in vivo and in vitro assays, and the female rat as an animal model, to determine whether Eap1 gene expression is regulated by ovarian steroids. Eap1 mRNA abundance decreases in both the hypothalamus and cerebral cortex during the infantile-juvenile phases of development, but it increases selectively in the hypothalamus at puberty, suggesting that in contrast to the general decline in expression observed in immature animals, the region-specific increase in Eap1 mRNA levels that occurs at puberty might be elicited by ovarian steroids.

Catecholamine reuptake inhibition causes weight loss by increasing locomotor activity and thermogenesis.

Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure.

Deletion of the Ttf1 gene in differentiated neurons disrupts female reproduction without impairing basal ganglia function.

Thyroid transcription factor 1 (TTF1) [also known as Nkx2.1 (related to the NK-2 class of homeobox genes) and T/ebp (thyroid-specific enhancer-binding protein)], a homeodomain gene required for basal forebrain morphogenesis, remains expressed in the hypothalamus after birth, suggesting a role in neuroendocrine function. Here, we show an involvement of TTF1 in the control of mammalian puberty and adult reproductive function.

Neuroendocrine mechanisms controlling female puberty: new approaches, new concepts.

Sexual development and mature reproductive function are controlled by a handful of neurones that, located in the basal forebrain, produce the decapeptide luteinizing hormone releasing hormone (LHRH). LHRH is released into the portal system that connects the hypothalamus to the pituitary gland and act on the latter to stimulate the synthesis and release of gonadotrophin hormones. The pubertal activation of LHRH release requires coordinated changes in excitatory and inhibitory inputs to LHRH-secreting neurones.

Hypothalamic tumor necrosis factor-alpha converting enzyme mediates excitatory amino acid-dependent neuron-to-glia signaling in the neuroendocrine brain.

Glial erbB1 receptors play a significant role in the hypothalamic control of female puberty. Activation of these receptors by transforming growth factor alpha (TGFalpha) results in production of prostaglandin E2, which then stimulates luteinizing hormone releasing hormone (LHRH) neurons to secrete LHRH, the neuropeptide controlling sexual development. Glutamatergic neurons set in motion this glia-to-neuron signaling pathway by transactivating erbB1 receptors via coactivation of AMPA receptors (AMPARs) and metabotropic glutamate receptors (mGluRs).

Minireview: the neuroendocrine regulation of puberty: is the time ripe for a systems biology approach?

The initiation of mammalian puberty requires an increase in pulsatile release of GnRH from the hypothalamus. This increase is brought about by coordinated changes in transsynaptic and glial-neuronal communication. As the neuronal and glial excitatory inputs to the GnRH neuronal network increase, the transsynaptic inhibitory tone decreases, leading to the pubertal activation of GnRH secretion.

Genes involved in the neuroendocrine control of normal puberty and abnormal puberty of central origin.

There is now compelling evidence that both normal puberty and disturbed pubertal development of central origin are, to a significant extent, determined by genetic factors. Although delayed sexual development can result from a deficient pituitary responsiveness to GnRH caused by mutations in the GnRH receptor gene, until recently the only genetically determined hypothalamic defects known to affect puberty were those caused by mutations in genes required for the migration of gonadotropin releasing hormone (GnRH) neurons, such as KAL1, FGFR1, and NELF. Recently, mutations in a gene termed GPR54 were identified as causing isolated hypogonadotrophic hypogonadism (IHH), due to a functional, instead of a structural hypothalamic defect.

Hypothalamic hamartoma: a paradigm/model for studying the onset of puberty.

This article discusses the potential mechanisms by which hypothalamic hamartomas (HHs) are formed and cause precocious puberty. The hypothesis is presented suggesting that HHs accelerate sexual development by producing bioactive substances that mimic - in an accelerated time-course - the cascade of events underlying the normal initiation of puberty. It is also proposed that because HHs contain key transcriptional and signaling networks required to initiate and sustain a pubertal mode of gonadotropin-releasing hormone (GnRH) release, they are able to trigger the pubertal process at an earlier age.

erbB-1 and erbB-4 receptors act in concert to facilitate female sexual development and mature reproductive function.

Glial erbB-1 and erbB-4 receptors are key components of the process by which neuroendocrine glial cells control LHRH secretion and the onset of female puberty. We now provide evidence that these two signaling systems work in a coordinated fashion to control reproductive function. To generate animals carrying functionally impaired erbB-1 and erbB-4 receptors, we crossed Waved 2 (Wa-2+/+) mice harboring a point mutation of the erbB-1 receptor with mice expressing a dominant-negative erbB-4 receptor in astrocytes.

Beyond the signal sequence: protein routing in health and disease.

Receptors, hormones, enzymes, ion channels, and structural components of the cell are created by the act of protein synthesis. Synthesis alone is insufficient for proper function, of course; for a cell to operate effectively, its components must be correctly compartmentalized. The mechanism by which proteins maintain the fidelity of localization warrants attention in light of the large number of different molecules that must be routed to distinct subcellular loci, the potential for error, and resultant disease.

Expression of alpha 4 and alpha 7 nicotinic receptors in the brainstem of female rabbits after coitus.

Coital signaling in the female rabbit involves sequential events in the brainstem and hypothalamus, resulting in a massive release of hypothalamic gonadotropin-releasing hormone (GnRH) that peaks within 1-2 h after mating. The neural connections between coitus and GnRH release involves norepinephrine (NE) and acetylcholine (ACh) since administration of antagonists against NE (dibenamine or phentolamine) or ACh (atropine, alpha-bungarotoxin (alpha-BTX) or scopolamine) blocks or attenuates ovulating events. Moreover, hypothalamic NE release and brainstem tyrosine hydroxylase (TH, the rate-limiting enzyme for NE synthesis) expression in the noradrenergic areas increase prior to, or in concert with, the preovulatory GnRH surge.

The neurobiology of female puberty.

In this review, studies are described indicating that the increase in pulsatile release of gonadotropin releasing hormone that signals the initiation of puberty requires both changes in transsynaptic communication and the activation of glia-to-neuron signaling pathways. The major players in the transsynaptic control of puberty are neurons that utilize excitatory and inhibitory amino acids as transmitters. Glial cells employ a combination of trophic factors and small cell-cell signaling molecules to regulate neuronal function and thus promote sexual development.

Glia-to-neuron signaling and the neuroendocrine control of female puberty.

The sine qua non event of puberty is an increase in pulsatile release of gonadotrophin hormone releasing hormone (GnRH). It is now clear that this increase and, therefore, the initiation of the pubertal process itself, require both changes in transsynaptic communication and the activation of glia-to-neuron signaling pathways. While neurons that utilize excitatory and inhibitory amino acids as transmitters represent major players in the transsynaptic control of puberty, glial cells utilize a combination of trophic factors and small cell-cell signaling molecules to regulate neuronal function and, thus, promote sexual development.

Progesterone as a mediator of gonadotrophin action in the corpus luteum: beyond steroidogenesis.

Studies using newer, potent GnRH antagonists and pure gonadotrophins have clarified the importance of: (i) the strength-duration of the midcycle surge of pituitary gonadotrophins (LH, FSH) in follicle rupture and conversion to the corpus luteum; (ii) the continued requirement for pituitary LH throughout development and the functional lifespan of the primate corpus luteum in the menstrual cycle; and (iii) the exponential secretion of chorionic gonadotrophin (CG) by the developing placenta to extend the functional lifespan of the primate corpus luteum in early pregnancy. Although studies continue to increase current understanding of the cellular and molecular actions of LH/CG to stimulate luteal steroidogenesis, knowledge of the processes whereby these gonadotrophins promote the development and maintenance of the functional corpus luteum remains limited. This review summarizes evidence that the primate ovulatory follicle and corpus luteum is a target for the primary steroid produced by luteinizing/luteal tissue (i.

Neuron-to-glia signaling mediated by excitatory amino acid receptors regulates ErbB receptor function in astroglial cells of the neuroendocrine brain.

Hypothalamic astroglial erbB tyrosine kinase receptors are required for the timely initiation of mammalian puberty. Ligand-dependent activation of these receptors sets in motion a glia-to-neuron signaling pathway that prompts the secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development, from hypothalamic neuroendocrine neurons. The neuronal systems that may regulate this growth factor-mediated back signaling to neuroendocrine neurons have not been identified.

Injection of soluble vascular endothelial growth factor receptor 1 into the preovulatory follicle disrupts ovulation and subsequent luteal function in rhesus monkeys.

Remarkable changes in vascular permeability and neovascularization occur within the ovulatory, luteinizing follicle. To evaluate the importance of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in periovulatory events, sequential experiments were designed in which vehicle (PBS/0.1% BSA; controls, n = 13) or a low dose (1.