Peptides (v.22, #5)

Editorial by John Kasckow (703).

Regulation of corticotropin-releasing hormone in vitro by M Pisarska; J.J Mulchahey; S Sheriff; T.D Geracioti; J.W Kasckow (705-712).
Studies examining regulation of corticotropin-releasing hormone (CRH) in vitro have been used to validate findings obtained in vivo and more importantly have been used as model systems to better understand signalling mechanisms responsible for the expression of the CRH gene and peptide. Most in vitro studies examining CRH have utilized hypothalamic tissue while a few have focused on the amygdala. Furthermore, clonal cell lines have also been utilized as models of central nervous system CRH neurons. Stimuli that have been implicated in regulating hypothalamic CRH in vitro include protein kinase A (PKA) and protein kinase C (PKC) activators, glucocorticoids, biogenic amines, cytokines and the gaseous neurotransmitters. CRH levels in the amygdala in vitro are affected by some of the same stimuli that regulate hypothalamic CRH; however there is evidence supporting differential regulation of CRH in these two brain regions by some of the same stimuli. Only a few studies in aggregate have investigated the signal transduction mechanisms responsible for CRH expression. These mechanistic studies have focused on PKA- and glucocorticoid-mediated changes in CRH expression. Clearly much more investigative work in better understanding CRH regulation in vitro is needed.
Keywords: Corticotropin-releasing hormone; In vitro; Culture; Amygdala; Hypothalamus; Stress;

The role of CRH in behavioral responses to stress by Gennady N Smagin; Stephen C Heinrichs; Adrian J Dunn (713-724).
Corticotropin-releasing hormone (CRH) and urocortin in the central nervous system affect behavior and can enhance behavioral responses to stressors. The action of CRH-related peptides is mediated through multiple receptors that differ markedly in their pharmacological profiles and anatomical distribution. Comparative pharmacology of CRH receptor agonists suggests that CRH, urocortin, sauvagine and urotensin consistently mimic, and CRH receptor antagonists consistently lessen, functional consequences of stressor exposure. Recently, important advances have been made in understanding the CRH system and its role in behavioral responses to stress by the development of specific CRH receptor antagonists, application of antisense oligonucleotides and development of transgenic mice lacking peptides and functional receptors. This review summarizes recent findings with respect to components of the CRH system and their role in stress-induced behavioral responses.
Keywords: Corticotropin-releasing factor; Urocortin; Antagonists; CRH receptors; Antisense; Stress; Behavior;

The physiology of corticotropin-releasing hormone deficiency in mice by Louis J Muglia; Lauren Jacobson; Stacie C Weninger; Katia P Karalis; Kyeong-Hoon Jeong; Joseph A Majzoub (725-731).
A review of the generation and characterization of corticotropin-releasing hormone (CRH)-deficient mice is presented. The studies summarized demonstrate the central role of CRH in the pituitary-adrenal axis response to stress, circadian stimulation, and glucocorticoid withdrawal. Additionally, pro-inflammatory actions of CRH at sites of local inflammation are given further support. In contrast, behavioral effects during stress that had been ascribed to CRH action are not altered in CRH-deficient mice. The normal behavioral response to stress in CRH-deficient mice strongly suggests the importance of other, possibly as yet undiscovered, CRH-like molecules.
Keywords: adrenal; circadian rhythm; glucocorticoids; knockout mice; pituitary;

This review highlights new information gained from studies using recently developed animal models that harbor specific alterations in corticotropin-releasing hormone (CRH) pathways. We discuss features of a transgenic mouse model of chronic CRH overexpression and two mouse models that lack either CRH receptor type 1 (CRH-R1) or type 2 (CRH-R2). Together these models provide new insights into the role of CRH pathways in promoting stability through adaptive changes, a process known as allostasis.
Keywords: Allostasis; Corticotropin-releasing hormone; Knock-out mice; Stress; Transgenic; Urocortin;

Mouse models of altered CRH-binding protein expression by Audrey F. Seasholtz; Heather L. Burrows; I.Jill Karolyi; Sally A. Camper (743-751).
CRH is the key physiological mediator of the endocrine, autonomic, and behavioral responses to stress. The recent characterization of urocortin, a new mammalian CRH-like ligand, adds to the complexity of the CRH system. Both CRH and urocortin mediate their endocrine and/or synaptic effects via two classes of CRH receptors. Similarly, both CRH and urocortin bind to the CRH-binding protein (CRH-BP). This secreted binding protein is smaller than the CRH receptors, but binds CRH and urocortin with an affinity equal to or greater than that of the receptors, and blocks CRH-mediated ACTH release in vitro. Several regions of CRH-BP expression colocalize with sites of CRH synthesis or release, suggesting that this binding protein may have a profound impact on the biological activity of CRH (or urocortin). While in vitro and in vivo studies have characterized the biochemical properties and regulation of the CRH-BP, animal models of altered CRH-BP expression can provide additional information on the in vivo role of this important modulatory protein. This review focuses on three mouse models of CRH-BP overexpression or deficiency. These animal models show numerous physiological changes in the HPA axis and in energy balance, with additional alterations in anxiogenic behavior. These changes are consistent with the hypothesis that CRH-BP plays an important in vivo modulatory role by regulating levels of “free” CRH and other CRH-like peptides in the pituitary and central nervous system.

Molecular biology of the CRH receptors— in the mood by Frank M Dautzenberg; Gavin J Kilpatrick; Richard L Hauger; Jean-Luc Moreau (753-760).
Dysfunctioning of corticotropin-releasing hormone (CRH) and its receptors (CRH1 and CRH2) has been linked to the development of stress-related disorders, such as mood and eating disorders. The molecular characterization of CRH1 and CRH2 receptors and their splice variants has generated detailed information on their pharmacology, tissue distribution and physiology. While mammalian CRH1 receptors nonselectively bind CRH analogs, the ligand specificity of CRH2 is narrower. CRH1 receptors are predominantly expressed in the brain and pituitary, whereas CRH2 receptor expression is limited to particular brain areas and to some peripheral organs. Molecular approaches to block CRH1 receptor expression in the brain argue in favor of its involvement in the regulation of some aspects of the stress response. The CRH receptor may be more important for motivational types of behavior essential for survival, such as feeding and defense.
Keywords: Corticotropin-releasing hormone; CRH receptor; alternative splicing; CRH binding pocket; CRH receptor deficient mice;

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is the main defining feature of the stress response. The primary mediator of this response is corticotropin-releasing hormone (CRH), a 41-residue peptide acknowledged as the principal hypophysiotropic factor driving stress-induced adrenocorticotropic hormone (ACTH) secretion. Although CRH is widely distributed within the central nervous system (CNS), the paraventricular nucleus (PVN) of the hypothalamus is the principal site of the parvocellular neurosecretory neurons responsible for delivering CRH to the hypophyseal portal system, an event that initiates the activity of the pituitary-adrenal axis. Stress-induced transcriptional activation of CRH takes place quite uniquely in this hypothalamic nucleus, despite the robust constitutive hybridization signal for CRH mRNA across the brain. The fact that CRH itself is capable of mimicking these effects and that de novo but transient expression of its type one receptor occurs in the PVN are data that make this hypothalamic region of great interest to study the mechanisms that lead to such specific transcriptional activity. This review will present evidence of such phenomenon by stressors of different categories as well as the possible neuromediators involved.
Keywords: Hypothalamus; hnRNA; Immune response; Stress; Rats; Glucocorticoids;

Regulation of pituitary corticotropin releasing hormone receptors by Greti Aguilera; Cristina Rabadan-Diehl; Maria Nikodemova (769-774).
Corticotropin releasing hormone (CRH) stimulates pituitary ACTH secretion through type-1 CRH (CRH1) receptors. Stimulation of the hypothalamic pituitary adrenal (HPA) axis as well as increased corticotroph responsiveness during stress and adrenalectomy are associated with marked pituitary CRH binding downregulation. The presence of CRH1 receptors in the pituitary are essential to maintain ACTH secretion. Downregulation of CRH binding is associated with normal or elevated levels of CRH1 receptor mRNA and this may contribute to the maintainence of permissive levels of CRH1 receptors in the pituitary. Injection of either CRH or glucocorticoids in rats in vivo induces CRH binding and CRH1 receptor mRNA downregulation, whereas their simultaneous administration causes only transient CRH1 receptor mRNA loss. Vasopressin increases CRH1 receptor mRNA levels. This suggest that interactions between CRH, vasopressin and glucocorticoids accounts for CRH1 receptor mRNA upregulation during stress. The lack of correlation between CRH binding and CRH1 receptor mRNA indicates that the major sites for pituitary CRH1 receptor regulation are at the post-transcriptional level.
Keywords: Corticotropin releasing hormone receptor type-1; pituitary; CRH receptor binding; CRH receptor mRNA; CRH receptor regulation;

This review will describe effects of corticosterone on the temporal dynamics of components within the hypothalamo-pituitary-adrenal (HPA) axis in response to sustained hypovolemia. The characterization of the synthetic and secretory profiles of HPA elements in these rat models reveals the complexities of steroid-mediated regulation of neuroendocrine and corticotrope function during a sustained stress event. Collectively, our data suggest activation of gene transcription and secretion are independently controlled, and that corticosterone affects adrenocorticotropin hormone (ACTH) gene expression in the parvicellular neuroendocrine part of the hypothalamic paraventricular nucleus using two mechanisms: first, an inhibition which contributes to classic negative feedback, and second, a facilitation, which is seen at low plasma concentrations.
Keywords: CRH; Vasopressin; Gene transcription; Hypovolemia; ACTH; Paraventricular;

Endometrial and myometrial corticotropin-releasing hormone (CRH): its regulation and possible roles by Achille Gravanis; Antonis Makrigiannakis; Emmanuel Zoumakis; Andrew N Margioris (785-793).
In human endometrium, both epithelial and stroma cells produce corticotropin-releasing hormone (CRH). Both types of cells also possess specific CRH-binding sites indicating a local effect of endometrial CRH. The transcription of the CRH gene in human endometrium is under the control of steroid hormones and locally produced prostanoids and interleukins. Endometrial CRH interacts with locally produced prostaglandins and interleukins. Based on these observations it can be hypothesized that CRH, prostaglandins and interleukins form a network responsible for the communication between epithelial and stromal cells, at the level of the endometrium, and between endometrial and myometrial cells at the level of uterus. The net product of these interaction is the micro-regulation of the decidualizing process and the preparation of endometrium for the implantation/nidation of the conceptus. Indeed, this network may represent the core of the intrauterine neuroendocrine—immune interactions involved in the decidualization of stroma and implantation of blastocyst. In addition, this network appears to be essential for the fine-tuning of myometrial tone.
Keywords: CRH; Uterus; Decidualization; Implantation; Labour;

The regulation of human corticotrophin-releasing hormone gene expression in the placenta by Bruce R King; Roger Smith; Richard C Nicholson (795-801).
Corticotrophin-releasing hormone (CRH) is a 41 amino acid neuropeptide that is expressed in the hypothalamus and the human placenta. Placental CRH production has been linked to the determination of gestational length in the human. Although encoded by a single copy gene, CRH expression in the placenta is regulated differently to the hypothalamus. Glucocorticoids stimulate CRH promoter activity in the placenta but inhibit it’s activity in the hypothalamus, via mechanisms involving different regions of the CRH promoter. We discuss how various stimuli alter CRH promoter activity and why these responses are unique to the placenta.
Keywords: cAMP; Glucocorticoids; Steroid hormones; AP-1; Ecdysone;

CRH in chronic inflammatory stress by David S Jessop; Michael S Harbuz; Stafford L Lightman (803-807).
Corticotropin-releasing hormone (CRH) is an important regulator of inflammation at the central level through hypothalamo-pituitary-adrenal (HPA) axis control of glucocorticoid secretion. Integrity of the HPA axis during autoimmune disease is critical in controlling the severity of inflammation, but the evidence for an HPA axis defect in the etiology of autoimmune diseases is not compelling. CRH secreted from leukocytes and neuronal terminals in peripheral tissues also plays a role in mediating inflammation. Elucidating the pathways underlying the expression of CRH, both central and peripheral, and interactions of CRH with other inflammatory mediators such as substance P, confers great potential for the development of a new generation of anti-inflammatory agents.
Keywords: CRH; Inflammation; Stress; Substance P;

Immunological and cellular stress signals trigger the release of corticotropin-releasing hormone (CRH) from the spleen, thymus and inflamed tissue. In vivo and in vitro studies generally suggest that peripheral, immune CRH has pro-inflammatory effects and acts in a paracrine manner by binding to CRH-R1 and CRH-R2 receptors on neighboring immune cells. However, it now seems likely that some of the suggested pro-inflammatory actions of CRH may be attributed to novel CRH-like peptides or to the related peptide, urocortin, which is also present in immune cells and has especially high affinity for CRH-R2 receptors.
Keywords: CRH; Urocortin; CRH-like peptides; CRH receptors; Peripheral immune system; Inflammation;

Cardiovascular actions of CRH and urocortin: an update by David G Parkes; Richard S Weisinger; Clive N May (821-827).
Urocortin is a potent regulator of cardiac function, with actions that are prolonged in experimental animals. These changes are mediated via binding to CRH receptors found in peripheral tissues. The diversity of actions of urocortin on behaviour, appetite, inflammation and the cardiovascular system suggest that this peptide may be an endogenous factor mediating actions previously attributed to CRH. The present review will focus on the recent understanding of mechanisms mediating the cardiovascular actions of urocortin and CRH reported to date.
Keywords: Urocortin; CRH; Hemodynamics; Appetite; Sheep;

Pretreatment with glucose increases entry of urocortin into mouse brain by Abba J Kastin; Victoria Akerstrom (829-834).
Although urocortin is a potent inhibitor of food ingestion after peripheral administration, it was recently shown that under normal conditions this peptide crosses the blood-brain barrier (BBB) at a very slow rate. We examined whether hyperglycemia could stimulate the rate of entry (Ki) of 125I-urocortin into the mouse brain. In euglycemic mice, 125I-urocortin injected iv entered the brain at a rate similar to that of the vascular marker 99mTc-albumin. However, injection of glucose (3 g/kg, ip) 0.5, 1, or 2 h before the 125I-urocortin greatly increased the influx of urocortin. Without the glucose, the self-inhibition characteristic of a saturable transport system was not apparent. Self-inhibition could be demonstrated after the glucose injection, indicating activation of a transport system for urocortin that was saturable. Injection of insulin (10 U/kg, ip) 1 or 2 h before the 125I-urocortin decreased the Ki. Thus, the entry of urocortin into brain can be activated by changes in the concentration of blood glucose, illustrating the responsiveness of the BBB to regulatory influences.
Keywords: Urocortin; Blood-brain barrier; Glucose; Insulin; Streptozotocin; Satiety; Peptide;

Increasing evidence suggests that the neuroendocrine changes seen in psychiatric patients, especially in those suffering from affective disorders, may be causally related to the psychopathology and course of these clinical conditions. The most robustly confirmed neuroendocrine finding among psychiatric patients with affective disorders is hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system, resulting from hyperactive hypothalamic corticotropin-releasing hormone (CRH) neurons. A large body of preclinical and clinical evidence suggests that both genetic and environmental factors contribute to the development of these HPA system abnormalities. Further, normalization of HPA system regulation was shown to be a prerequisite for favorable treatment response and stable remission among depressives. Preclinical data based on animal models including selectively bred rat lines and mouse mutants support the notion that CRH neurons are hyperactive also in neuroanatomical regions that are involved in behavioral regulation but are located outside the neuroendocrine system. This raises the question of whether more direct interventions such as CRH receptor antagonists would open a new lead in the treatment of stress-related disorders such as depression, anxiety and sleep disorders. Recent clinical observations support this possibility.
Keywords: Stress; Depression; Anxiety; Corticotropin-releasing hormone; Corticotropin-releasing factor; Corticotropin-releasing hormone receptor antagonist; Hypothalamic-pituitary-adrenocortical (HPA) system; Antidepressant;

Corticotropin-releasing hormone in depression and post-traumatic stress disorder by J.W. Kasckow; D. Baker; T.D. Geracioti (845-851).
Corticotropin-releasing hormone (CRH) has been implicated in the regulation of a wide range of behaviors including arousal, motor function, feeding, and reproduction. Because depressed patients are often hypercortisolemic and intracerebroventricular administration of CRH to experimental animals produces a syndrome reminiscent of depression, dysregulation of this compound has been suggested to be involved in the pathogenesis of depressive and anxiety disorders. Studies of cerebrospinal fluid CRH levels and clinical neuroendocrine tests in patients with anxiety and affective disorders have supported this hypothesis. This review discusses these neuroendocrine findings in melancholic and atypical depression as well as post-traumatic stress disorder (PTSD). Overall, the data suggest that melancholic depression is characterized by hyperactive central CRH systems with overactivity of the pituitary-adrenal (HPA) axis. On the other hand, atypical depression is characterized by hypoactive central CRH systems and accompanying underactivity of the hypothalamic-pituitary-adrenal axis. Furthermore, the neuroendocrinology of PTSD appears to be unique, in that patients have hyperactive central CRH systems with underactivity of the pituitary-adrenal axis.
Keywords: Corticotropin-releasing hormone; Depression; Atypical depression; Melancholic depression; Post-traumatic stress disorder; Hypothalamic-pituitary-adrenal axis; Cerebrospinal fluid; ACTH; Cortisol;