Recent Progress In Hormone Research[JOURNAL]
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200 papers
Nitric oxide signaling: would you believe that a simple free radical could be a second messenger, autacoid, paracrine substance, neurotransmitter, and hormone?
Murad F
Recent Prog Horm Res · 1998 · PMID 9769702
Nitric oxide signaling during the past two decades has been one of the most rapidly growing areas in biology. This simple free radical gas with an unshared electron can regulate an ever-growing list of biological process...
Nitric oxide signaling during the past two decades has been one of the most rapidly growing areas in biology. This simple free radical gas with an unshared electron can regulate an ever-growing list of biological processes. In most instances, nitric oxide mediates its biological effects by activating guanylyl cyclase and increasing cyclic GMP synthesis. However, effects of nitric oxide that are independent of cyclic GMP are also growing at a rapid rate. Nitric oxide can interact with transition metals such as iron, thiol groups, other free radicals, oxygen, superoxide anion, unsaturated fatty acids, and other reactive species. The effects of nitric oxide can mediate important physiological regulatory events in cell regulation, cell-cell communication, and signaling. However, as with any messenger molecule, there can be too much or too little of the substance and pathological events ensue. Methods to regulate either nitric oxide formation, metabolism, or function have been used therapeutically for more than a century, as with nitroglycerin therapy. Current and future research should permit the development of an expanded therapeutic armamentarium for the physician to manage effectively a number of important disorders. These expectations have undoubtedly fueled the vast research interests in this simple molecule.
Alpha 2-adrenergic receptor subtypes: subtle mutation of the alpha 2A-adrenergic receptor in vivo by gene targeting strategies reveals the role of this subtype in multiple physiological settings.
MacMillan LB, Lakhlani P, Lovinger D … +1 more , Limbird LE
Recent Prog Horm Res · 1998 · PMID 9769701
Alpha 2-adrenergic receptors (alpha 2AARs) are coupled by pertussis-toxin sensitive G proteins to various effectors, including adenylyl cyclase and ion channels. The alpha 2AARs respond to endogenous norepinephrine and e...
Alpha 2-adrenergic receptors (alpha 2AARs) are coupled by pertussis-toxin sensitive G proteins to various effectors, including adenylyl cyclase and ion channels. The alpha 2AARs respond to endogenous norepinephrine and epinephrine to elicit a variety of physiological responses, including inhibition of neurotransmitter release, suppression of insulin release from pancreatic beta cells, activation of platelet aggregation, and contraction of arteriolar smooth muscle. Three distinct alpha 2AR subtypes (alpha 2A, alpha 2B, alpha 2C) have been characterized by both pharmacological and molecular biological approaches; however, the lack of subtype-specific ligands has precluded an understanding of the physiological relevance of each subtype. Previous studies demonstrated that mutation of a conserved aspartate residue in the alpha 2AAR to asparagine (D79N alpha 2AAR) resulted in a receptor that retained its ability to inhibit voltage-gated Ca2+ channels and cAMP production but was unable to activate K+ currents in AtT20 cells (Surprenant et al., 1992). To explore the physiological role of the alpha 2AAR subtype and to evaluate the selectivity of alpha 2AAR effects with respect to various signal transduction pathways, we used gene targeting in embryonic stem cells to create a mouse line that expresses the mutant D79N alpha 2AAR instead of the wild-type alpha 2AAR. We established a D79N alpha 2AAR mouse line and characterized various alpha 2AAR-mediated physiological functions in these mutant mice. Because the in vivo D79N alpha 2AAR is expressed at a reduced density relative to wild-type alpha 2A and is not selectively uncoupled from a single signal transduction pathway, our findings of losses of alpha 2AAR-mediated functions in the D79N mice reflect a requirement for the alpha 2AAR subtype but do not reveal the importance of a specific signal transduction pathway. The alpha 2AAR subtype appears to mediate reduction in blood pressure following alpha 2A agonist administration as well as sedative, anesthetic-sparing, and analgesic responses to alpha 2AAR agonists. Therefore, the alpha 2AAR subtype appears to mediate a majority of the clinically relevant responses associated with alpha 2AAR agonist treatment.
Regulation of gene expression in the endocrine heart.
Durocher D, Grépin C, Nemer M
Recent Prog Horm Res · 1998 · PMID 9769700
Cardiac growth and contractility is profoundly altered in response to various hormones and neurotransmitters as well as by changes in electrolyte balance, blood volume, and blood pressure. In turn, the endocrine heart co...
Cardiac growth and contractility is profoundly altered in response to various hormones and neurotransmitters as well as by changes in electrolyte balance, blood volume, and blood pressure. In turn, the endocrine heart contributes to body homeostasis by secreting a number of biologically active peptide hormones that act on several target tissues. Atrial natriuretic peptide (ANP) and B-type natiuretic peptide (BNP) are the major secretory products of the endocrine myocardium. These peptide hormones act on many target organs via guanylate cyclase-linked membrane receptors to produce natriuresis, diuresis, vasodilatation, and hypotension. ANP and BNP receptors are found on most organs involved in cardiovascular homeostasis (e.g., kidney, adrenal, vasculature, brain). They are also present in gonads and in pituitary, where they alter steroidogenesis and pituitary hormone secretion. Not surprisingly, changes in blood pressure, volume, or hormone status influence ANP and BNP expression, which is also altered in almost all diseases that affect cardiac function. Thus, studies of ANP and BNP gene expression are relevant for many clinical settings. Moreover, transcription of the ANP and BNP genes characterizes cardiac cells at very early stages of development and is tightly linked to cardiac growth--be it proliferation, as in the fetal heart, or trophic growth, as in postnatal ventricular hypertrophy. Thus, analysis of the molecular circuitry that controls ANP and BNP expression might shed important insight into the complex regulatory pathways that underlie normal and pathologic heart development. Indeed, over the past few years, we have analysed transcriptional control of the ANP and BNP genes in embryonic and postnatal cardiomyocytes and in cardiomyocytes treated with hormones and neurotransmitters that cause cardiomyocyte hypertrophy. These studies have lead to the identification of distinct cis-acting DNA elements that modulate basal and hormone-stimulated transcription. Most importantly, the work also resulted in the isolation and characterization of cardiac-specific transcription factors that play critical roles for cardiac cell differentiation and survival.
Salt in hypertension: physiological and molecular aspects.
Gavras I, Gavras H
Recent Prog Horm Res · 1998 · PMID 9769699
Salt loading acutely or chronically raises blood pressure in susceptible individuals. Sodium-dependent hypertension is characterized by sympathetic stimulation, apparently mediated via excitation of alpha 2-adrenergic re...
Salt loading acutely or chronically raises blood pressure in susceptible individuals. Sodium-dependent hypertension is characterized by sympathetic stimulation, apparently mediated via excitation of alpha 2-adrenergic receptors in brainstem nuclei. At this time, it is unclear which one(s) of the three alpha 2-adrenoceptor subtypes may be involved in this process. Although some studies have reported increases in numbers and/or functional responsiveness of alpha 2-adrenoceptors in hypertensives or normotensive offspring of hypertensive parents, others have failed to confirm this. Genetic analysis has suggested presence of alpha 2-adrenoceptor gene polymorphisms in some hypertensives but the results so far have been inconsistent.
Recent progress in hormone research. Proceedings of the 1996 conference.
Recent Prog Horm Res · 1997 · PMID 9273595
Abstract loading — click title to view on PubMed.
Brain gonadotropin releasing hormone receptors: localization and regulation.
Jennes L, Eyigor O, Janovick JA … +1 more , Conn PM
Recent Prog Horm Res · 1997 · PMID 9238864
In this review, the current information about the location of GnRH receptor protein and GnRH receptor mRNA in the rat central nervous system is summarized as well as the changes that occur in the GnRH receptor mRNA level...
In this review, the current information about the location of GnRH receptor protein and GnRH receptor mRNA in the rat central nervous system is summarized as well as the changes that occur in the GnRH receptor mRNA levels during different endocrine conditions of the animals. The results of these studies show that GnRH receptor protein and mRNA levels change in parallel in the hippocampus, suggesting that pretranscriptional factors control the synthesis of the receptor. In the arcuate and ventromedial nuclei of the hypothalamus, GnRH receptor mRNA levels are highest during the early morning of proestrus and during the morning of an estrogen-progesterone-induced LH surge. The timing of the changes in GnRH receptor mRNA levels indicates that increasing levels of estradiol are responsible for the increase in GnRH receptor synthesis. Binding of GnRH agonist to the brain GnRH receptor causes a dose-dependent increase in inositol phosphates as well as changes in intracellular Ca++ levels of the target neurons. Together, it is suggested that GnRH functions in the brain as a neurotransmitter and/or modulator linking the peripheral endocrine effects of GnRH to actions of the peptide inside the central nervous system where it can facilitate, for example, reproductive behaviors.
Changing through doing: behavioral influences on the brain.
White SA, Fernald RD
Recent Prog Horm Res · 1997 · PMID 9238863
It seems self-evident that the brain controls behavior but does behavior also "control" the brain? This chapter examines evidence that behavior can and does influence specific aspects of brain structure and function. Evi...
It seems self-evident that the brain controls behavior but does behavior also "control" the brain? This chapter examines evidence that behavior can and does influence specific aspects of brain structure and function. Evidence for such influence is easily obtained on an evolutionary time scale, since the selective forces found in the ecological niche of the animal are typically reflected in its sensory and motor activities as well as its body shape and behavioral habits. Similarly, during development, there is ample evidence that the behavior acts in concert with the environment to establish structural changes in the brain that last a lifetime. Perhaps most surprisingly there is now evidence that social behavior can cause changes in the brain in adult animals and that these changes are reversible. The changes caused by behavioral interactions can be dramatic and typically are related to reproductive behavior. Understanding the mechanisms responsible for dynamic changes in the nervous systems of adult animals is a major challenge and the discovery that it can occur may lead to insights about other systems where behavior sculpts the brain.
Interaction, signal generation, signal divergence, and signal transduction of LH/CG and the receptor.
Ji TH, Ryu KS, Gilchrist R … +1 more , Ji I
Recent Prog Horm Res · 1997 · PMID 9238862
The LH/CG receptor is comprised of two structurally and functionally distinct domains, extracellular N-terminal exodomain and membrane-embedded endodomain. These two domains can separately be expressed and processed, inc...
The LH/CG receptor is comprised of two structurally and functionally distinct domains, extracellular N-terminal exodomain and membrane-embedded endodomain. These two domains can separately be expressed and processed, including folding. The exodomain alone has the high-affinity hormone binding site but is not capable of generating hormonal signal. In contrast, the endodomain alone has the site for receptor activation. These two domains contact each other in holo-receptor and split receptor. This interaction, particularly through exoloops 2 and 3, constrains the high-affinity hormone binding at the exodomain. Conversely, the exodomain could be involved in receptor activation. Therefore, these two domains are not entirely independent, although they can be independently synthesized and processed. The existing evidence indicates that hCG and the receptor undergo multiple stages of interactions leading to receptor activation. Initial high-affinity binding of hCG to the exodomain results in conformational adjustments of the hCG/exodomain complex. This leads to the secondary, low-affinity contact of the hCG/exodomain complex with the endodomain. This secondary contact is responsible for generating signals. They are transduced through transmembrane domains (TM) to the cytoplasmic portion (cytoloops and the C-terminal tail) of the receptor and then transferred to cytoplasmic signaling molecules such as G protein. Mutations in the exodomain and endodomain (N-extension, exoloops, TM, cytoloops, and cytoplasmic tail) have the potential to interfere with receptor activation at different steps: signal generation, transduction, and transfer. Binding of hCG to the LH/CG receptor is known to induce two signals, one for adenylyl cyclase/ cAMP and the other for phospholipase C/inositol phosphate/diacylglycerol. The cAMP signal and IP signal diverge at the surface of the receptor. These independent signals are separately transduced through the transmembrane domains to the cytoplasmic part of the receptor, indicating the existence of the distinct transducers for each of the signals. Furthermore, it is likely that the divergent signals are separately transferred to cytoplasmic signal molecules such as G protein. In addition, each cAMP signal and IP signal consists of at least three separate subsignals: affinity signal, maximal production (efficacy) signal, and basal level signal. In heterodimeric hCG there are distinct parts responsible for high-affinity receptor binding and receptor activation. Particularly, the C-terminal residues of the alpha subunit play a crucial role in receptor activation. This alpha subunit is shared with other glycoprotein hormones, follicle-stimulating hormone, and thyroid-stimulating hormone. Interestingly, the alpha C-terminal residues play distinct roles in all three hormones, despite its common nature.
Anchoring and scaffold proteins for kinases and phosphatases.
Lester LB, Scott JD
Recent Prog Horm Res · 1997 · PMID 9238861
Many hormones mediate their intracellular actions by triggering signal transduction pathways that alter the phosphorylation state of key regulatory proteins. Protein phosphorylation is a reversible process involving two...
Many hormones mediate their intracellular actions by triggering signal transduction pathways that alter the phosphorylation state of key regulatory proteins. Protein phosphorylation is a reversible process involving two classes of signaling enzymes: protein kinases, which catalyze the transfer of phosphate from ATP onto substrate proteins, and phosphoprotein phosphatases, which perform the dephosphorylation step. To insure tight control of hormonally initiated phosphorylation events, the activity of multifunctional kinases and phosphatases is precisely regulated and responds to fluctuations in diffusible second messengers such as Ca2+, phospholipid, and cAMP. Another mechanism that contributes to their regulation is to restrict the location of these enzymes to certain subcellular compartments. Subcellular targeting enhances the selectivity of serine/threonine phosphatases and kinases by favoring their accessibility to certain substrate proteins. Compartmentalization is achieved through a "targeting moiety," which is defined as that part of a phosphatase or kinase that directs the catalytic subunit to a certain subcellular environment. The targeting moiety restricts the location of a phosphatase or kinase through association with a "targeting locus." These are often structural membrane proteins, cytoskeletal components, or cellular organelles. Targeting subunits for the type I phosphatase and protein kinase C have been identified; however, the focus of this chapter centers around a family of anchoring proteins, called AKAPs, that localize the type II cAMP-dependent protein kinase (PKA). Structure-function analysis suggest that each anchoring protein binds to the RII dimer through a conserved amphipathic helix region and is tethered to specific subcellular sites via association of a targeting domain with structural proteins or cellular organelles. Peptides patterned after the amphipathic region have been used to probe the functional significance of PKA anchoring inside cells and have begun to be established by that disruption RII/AKAP interaction in vivo has concomitant effects on certain PKA-mediated phosphorylation events. In addition, multivalent binding proteins such as AKAP79 and AKAP250 have been characterized and appear to serve as platforms for the assembly of kinase/phosphatase signaling complexes. Collectively, these studies suggest that the AKAPs represent a growing family of regulatory proteins that provide a molecular architecture that organizes the intracellular location of a single or multiple multifunctional kinase.
Regulation and properties of the rat Ca2+/calmodulin-dependent protein kinase IV gene and its protein products.
Means AR, Ribar TJ, Kane CD … +2 more , Hook SS, Anderson KA
Recent Prog Horm Res · 1997 · PMID 9238860
Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) is a monomeric multifunctional enzyme that is expressed only in subanatomical portions of the brain, T lymphocytes, and postmeiotic male germ cells. It is present in t...
Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) is a monomeric multifunctional enzyme that is expressed only in subanatomical portions of the brain, T lymphocytes, and postmeiotic male germ cells. It is present in the nucleus of the cells in which it is expressed and can phosphorylate and activate the cyclic AMP response element binding proteins CREB and CREM tau in a manner analogous to protein kinase A. In the absence of Ca2+/calmodulin, CaMKIV is inactive. Activation requires three events: 1) binding of Ca2+/calmodulin; 2) phosphorylation of a single threonine residue present in the activation loop by a separate protein kinase that is also Ca2+/calmodulin-dependent; and 3) autophosphorylation of serine residues present in the extreme N-terminus that is required to relieve a novel form of autoinhibition. The gene for rat CaMKIV has been cloned and found to span 42 kb of DNA. The gene encodes three proteins: namely, the alpha and beta forms of CaMKIV that differ only in that the beta form contains a 28 amino acid N-terminal extension as well as calspermin. Calspermin is the C-terminal 169 amino acids of CaMKIV that binds Ca2+/calmodulin and is expressed only in postmeiotic male germ cells. The promoter for calspermin resides in the penultimate intron of the CaMKIV gene and is regulated by two CREs. This promoter is sufficient to faithfully target expression of a reporter gene to the postmeiotic male germ cells of transgenic mice. Transgene expression can be induced in cells from the transgenic mice that do not normally express it by transfection of CREM tau and CaMKIV. These data suggest that rearrangement of chromatin during meiosis together with the expression of CREM tau at high levels are sufficient to control expression of the calspermin promoter during spermatogenesis. On the other hand, the developmental expression of CaMKIV in brain and thymus appears to be controlled by thyroid hormone mediated via the thyroid hormone receptor alpha. In T lymphocytes, CaMKIV will phosphorylate CREB in response to signals that result in T cell activation. Transgenic mice that express a kinase minus mutant of CaMKIV specifically in thymic T cells show a marked reduction of total thymic cellularity. The remaining T cells undergo a much greater than normal rate of spontaneous apoptosis when placed in culture. These cells fail to generate the signals to phosphorylate CREB and produce significantly less of the cytokine Interleukin-2 (IL-2) in response to agents that either increase intracellular Ca2+ and/or activate protein kinase C. Collectively, the data suggest that CaMKIV may be involved both in preventing apoptosis during T cell development and also in the early cascade of events that is required to activate the mature T cells in response to a mitogenic stimulus.
New concepts in extracellular signaling for insulin action: the single gateway hypothesis.
Bergman RN
Recent Prog Horm Res · 1997 · PMID 9238859
Insulin resistance is a precursor to and primary cause of Type 2 diabetes mellitus. In addition, insulin resistance is associated with other chronic diseases, including gestational diabetes, cardiovascular disease, and c...
Insulin resistance is a precursor to and primary cause of Type 2 diabetes mellitus. In addition, insulin resistance is associated with other chronic diseases, including gestational diabetes, cardiovascular disease, and cancer. Resistance to insulin's effects on carbohydrate metabolism include diminished actions of insulin to enhance glucose uptake and suppress endogenous glucose production. This chapter introduces new concepts related to the mechanism by which insulin stimulates glucose utilization in vivo and demonstrates that these processes are mechanistically linked to glucose production. Insulin acts rapidly in vitro to stimulate glucose uptake; in contrast, its effects in vivo are relatively slow in the conscious animal or human subject. The explanation for this difference between in vitro and in vivo dynamics is the delay associated with insulin transport across capillary endothelium of insulin-sensitive tissues (primarily muscle). Also, interstitial insulin is attenuated in concentration compared to plasma insulin at basal as well as under hyperinsulinemic conditions (plasma:interstitial ratio, 3:2). The sluggishness of insulin action and the attenuation in insulin concentration can be explained by a model in which transendothelial insulin transport is restricted and interstitial insulin binds to insulin-sensitive cells, where the hormone is internalized and degraded. Whether insulin transport occurs by a hormone-specific mechanism (i.e., via receptors on endothelial cells) was tested by comparing transport at physiological with pharmacological insulin concentrations-evidence supports a nonspecific mechanism of transport across endothelium (i.e., diffusion or transcytosis). Transendothelial transport alters the in vivo patterns of insulin signaling-biphasic plasma insulin after glucose injection is reflected in a simple, rapid increase in interstitial insulin to an elevated concentration. The time course of insulin's effect to suppress endogenous glucose output is a mirror image of its effect to enhance glucose uptake; however, there is no transendothelial barrier to insulin action at the liver. The similarity in action dynamics at periphery and liver was explained by a mechanism in which insulin crosses into peripheral tissue and alters a "second (blood-borne) signal" that, in turn, suppresses liver glucose production. Of various possible alternative candidates for the second signal, declining plasma free fatty acids appear to signal suppression of glucose production. We have proposed the "single gateway hypothesis" to explain insulin's action on carbohydrate metabolism in vivo: insulin crosses the endothelial boundary in skeletal muscle (to stimulate glucose disposal) and traverses the endothelial barrier in adipose tissue to suppress lipolysis. The declining free fatty acids are proposed to be a major factor in the insulin-mediated decline in glucose output. This mechanism can be contrasted with the classical concept that portal insulin controls the liver directly. Recent evidence supports the concept that, under normal levels of glucagonemia, less than 25% of the suppression of hepatic glucose output by insulin is due to a direct effect of insulin via the portal vein and that most of the effect (approximately 75%) is explained by the indirect single gateway mechanism. These results raise the question of whether hepatic insulin resistance in Type 2 diabetes can be explained by insulin resistance at the adipocyte, which causes a failure of reduction of FFA by insulin, leading to overproduction of glucose by the liver. The possible role of the single gateway mechanism in diabetes is under investigation.
The melatonin rhythm-generating enzyme: molecular regulation of serotonin N-acetyltransferase in the pineal gland.
Klein DC, Coon SL, Roseboom PH … +11 more , Weller JL, Bernard M, Gastel JA, Zatz M, Iuvone PM, Rodriguez IR, Bégay V, Falcón J, Cahill GM, Cassone VM, Baler R
Recent Prog Horm Res · 1997 · PMID 9238858
A remarkably constant feature of vertebrate physiology is a daily rhythm of melatonin in the circulation, which serves as the hormonal signal of the daily light/dark cycle: melatonin levels are always elevated at night....
A remarkably constant feature of vertebrate physiology is a daily rhythm of melatonin in the circulation, which serves as the hormonal signal of the daily light/dark cycle: melatonin levels are always elevated at night. The biochemical basis of this hormonal rhythm is one of the enzymes involved in melatonin synthesis in the pineal gland-the melatonin rhythm-generating enzyme-serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AA-NAT, E.C. 2.3.1.87). In all vertebrates, enzyme activity is high at night. This reflects the influences of internal circadian clocks and of light. The dynamics of this enzyme are remarkable. The magnitude of the nocturnal increase in enzyme activity ranges from 7- to 150-fold on a species-to-species basis among vertebrates. In all cases the nocturnal levels of AA-NAT activity decrease very rapidly following exposure to light. A major advance in the study of the molecular basis of these changes was the cloning of cDNA encoding the enzyme. This has resulted in rapid progress in our understanding of the biology and structure of AA-NAT and how it is regulated. Several constant features of this enzyme have become apparent, including structural features, tissue distribution, and a close association of enzyme activity and protein. However, some remarkable differences among species in the molecular mechanisms involved in regulating the enzyme have been discovered. In sheep, AA-NAT mRNA levels show relatively little change over a 24-hour period and changes in AA-NAT activity are primarily regulated at the protein level. In the rat, AA-NAT is also regulated at a protein level; however, in addition, AA-NAT mRNA levels exhibit a 150-fold rhythm, which reflects cyclic AMP-dependent regulation of expression of the AA-NAT gene. In the chicken, cyclic AMP acts primarily at the protein level and a rhythm in AA-NAT mRNA is driven by a noncyclic AMP-dependent mechanism linked to the clock within the pineal gland. Finally, in the trout, AA-NAT mRNA levels show little change and activity is regulated by light acting directly on the pineal gland. The variety of mechanisms that have evolved among vertebrates to achieve the same goal-a rhythm in melatonin-underlines the important role melatonin plays as the hormonal signal of environmental lighting in vertebrates.
Aging of the female reproductive system: a window into brain aging.
Wise PM, Kashon ML, Krajnak KM … +7 more , Rosewell KL, Cai A, Scarbrough K, Harney JP, McShane T, Lloyd JM, Weiland NG
Recent Prog Horm Res · 1997 · PMID 9238857
The menopause marks the permanent end of fertility in women. It was once thought that the exhaustion of ovarian follicles was the single, most important explanation for the transition to the menopause. Over the past deca...
The menopause marks the permanent end of fertility in women. It was once thought that the exhaustion of ovarian follicles was the single, most important explanation for the transition to the menopause. Over the past decade, this perception has gradually changed with the realization that there are multiple pacemakers of reproductive senescence. We will present evidence that lends credence to the hypothesis that the central nervous system is a critical pacemaker of reproductive aging and that changes at this level contribute to the timing of the menopause. Studies demonstrate that an increasing de-synchronization of the temporal order of neuroendocrine signals may contribute to the accelerated rate of follicular loss that occurs during middle age. We suggest that the dampening and destabilization of the precisely orchestrated ultradian, circadian, and infradian neural signals lead to miscommunication between the brain and the pituitary-ovarian axis. This constellation of hypothalamic-pituitary-ovarian events leads to the inexorable decline of regular cyclicity and heralds menopausal transition.
Mutations contributing to human blood pressure variation.
Karet FE, Lifton RP
Recent Prog Horm Res · 1997 · PMID 9238856
In spite of a large body of physiological, biochemical, and recently genetic investigations, the causes of hypertension remain largely unknown. Recognition that hypertension is, in part, genetically determined has motiva...
In spite of a large body of physiological, biochemical, and recently genetic investigations, the causes of hypertension remain largely unknown. Recognition that hypertension is, in part, genetically determined has motivated studies to identify mutations conferring susceptibility. To date, mutations in at least 10 genes have been shown to alter blood pressure. The majority are rare mutations responsible for various mendelian hyper- and hypotensive syndromes, imparting large quantitative effects. Those causing hypertension are glucocorticoid-remediable aldosteronism, the syndrome of apparent mineralocorticoid excess, and Liddle's syndrome. Conversely, pseudohypoaldosteronism type 1, Bartter's, and Gitelman's syndromes all cause hypotension. In addition, mutations in the angiotensinogen gene are associated with hypertension. All these mutations alter blood pressure through a common pathway, affecting salt and water reabsorption in the kidney. These findings demonstrate the place of molecular genetic approaches in elucidating the underlying determinants of human blood pressure variation and may provide insight into the physiological mechanisms underlying common forms of hypertension.
Mineralocorticoid receptors, salt, and hypertension.
Funder JW, Krozowski Z, Myles K … +3 more , Sato A, Sheppard KE, Young M
Recent Prog Horm Res · 1997 · PMID 9238855
This review, covering work from the Baker Institute and elsewhere, is divided into four sections. In the first a summary account of two areas-mineralocorticoid receptors and the enzyme 11 beta hyderoxysteroid dehydrogena...
This review, covering work from the Baker Institute and elsewhere, is divided into four sections. In the first a summary account of two areas-mineralocorticoid receptors and the enzyme 11 beta hyderoxysteroid dehydrogenase-will be given as background. Next is a brief consideration of the three single-gene causes of human hypertension described to date-glucocorticoid-remediable aldosteronism. Liddle's syndrome, and apparent mineralocorticoid excess-in all of which abnormal sodium handling is a feature. Third, the sequelae of aldosterone occupancy of nonepithelial mineralocorticoid receptors will be analyzed in some detail by reviewing studies on experimental mineralocorticoid hypertension and cardiac fibrosis from this laboratory and elsewhere. Finally, three recent studies from this laboratory will be presented: on putative 11-ketosteroid receptors in epithelial tissue, on glucose-PKC potentiation of mineralocorticoid effects on heart cells, and on the necessity for factors/ processes other than the conversion of cortisol to cortisone (or, in the rat, corticosterone to 11-dehydrocorticosterone) to ensure aldosterone-specific effects in mineralocorticoid target tissues.
Growth hormone-releasing hormone and growth hormone-releasing peptide as therapeutic agents to enhance growth hormone secretion in disease and aging.
Thorner MO, Chapman IM, Gaylinn BD … +2 more , Pezzoli SS, Hartman ML
Recent Prog Horm Res · 1997 · PMID 9238854
Growth hormone (GH) secretion is pulsatile and is tightly regulated. In this chapter the effects of aging, nutrition, the feedback effects of IGF-I, and the role of body composition in the decline of GH secretion will be...
Growth hormone (GH) secretion is pulsatile and is tightly regulated. In this chapter the effects of aging, nutrition, the feedback effects of IGF-I, and the role of body composition in the decline of GH secretion will be discussed. In GH-deficient adults there is an increase in the amount of intra-abdominal (visceral) fat. Similarly, with increasing age, there is an increase in visceral fat and there is a tight correlation between 24-hour GH release and visceral fat in the elderly. This may have serious metabolic consequences, including insulin resistance and increased cardiovascular risk. There are at least four potential mechanisms for the age-related decline in GH secretion: 1) decreased release of growth hormone releasing-hormone (GHRH); 2) increased release of somatostatin; 3) enhanced sensitivity to IGF-I feedback; and 4) decreased somatotroph mass. The latter two potential mechanisms are discussed. There is little evidence that there is any change in sensitivity to IGF-I feedback with aging and the somatotroph cell mass appears to be preserved in older subjects. The GH axis may be stimulated by either GHRH or by growth hormone-releasing peptide (GHRP) and related compounds. Chronic therapy with GHRH in GH-deficient children restores GH secretion and accelerates linear growth. Mutations of the GHRH receptor lead to GH deficiency and short stature. This indicates the essential role of GHRH in regulation of GH secretion. Growth hormone releasing peptide was discovered in 1981. Recently, the GHRP/GH secretagogue receptor has been cloned and orally active GHRP mimetics have been developed. One such compound, MK-677, stimulates pulsatile GH secretion and its effects persist for 24 hours. Oral administration of MK-677 for a month in the elderly demonstrates that this route stimulates a physiologic pattern of GH secretion. The amplitude of the GH pulses was increased but the number of GH pulses was unchanged. Thus, in older individuals, the amount of GH secreted in 24 hours is restored toward that seen in young adults. This compound also enhances GH secretion in GH-deficient adults who had been GH-deficient during childhood. The development of stable, orally active molecules to stimulate the GHRP/GH secretagogue receptor is a practical reality. These GH secretagogues may have a therapeutic role in short stature and adult GH deficiency. In addition, the use of GH secretagogues in normal aging merits investigation, as growth hormone may regulate body composition in older adults.
Aromatase expression in health and disease.
Simpson ER, Zhao Y, Agarwal VR … +8 more , Michael MD, Bulun SE, Hinshelwood MM, Graham-Lorence S, Sun T, Fisher CR, Qin K, Mendelson CR
Recent Prog Horm Res · 1997 · PMID 9238853
Family 19 of the P450 superfamily is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization, since it involves conversion of the delta 4-3-one A-ring o...
Family 19 of the P450 superfamily is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization, since it involves conversion of the delta 4-3-one A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. Its members occur throughout the entire vertebrate phylum. The reaction mechanism of aromatase is very interesting from a chemical point of view and has been studied extensively; however, a detailed examination of structure-function relationships has not been possible due to lack of a crystal structure. Recent attempts to model the three-dimensional structure of aromatase have permitted a model that accounts for the reaction mechanism and predicts the location of aromatase inhibitors. The gene encoding human aromatase has been cloned and characterized and shown to be unusual compared to genes encoding other P450 enzymes, since there are a number of untranslated first exons that occur in aromatase transcripts in a tissue-specific fashion, due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in ovary utilizes a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in placenta utilizes a distal promoter that is located at least 40 kb upstream of the start of transcription and that is regulated by retinoids. Other promoters are employed in brain and adipose tissue. In the latter case, class I cytokines such as IL-6 and IL-11 as well as TNF alpha are important regulatory factors. PGE2 is also an important regulator of aromatase expression in adipose mesenchymal cells via cAMP and PGE2 appears to be a major factor produced by breast tumors that stimulates estrogen biosynthesis in local mesenchymal sites. In all of the splicing events involved in the use of these various promoters, a common 3'-splice junction is employed that is located upstream of the start of translation; thus, the coding regions of the transcripts- and hence the protein-are identical regardless of the tissue site of expression; what differ in a tissue-specific fashion are the 5'-ends of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint as well as for the physiology and pathophysiology of estrogen formation. Recently, a number of mutations of the aromatase gene have been described, which give rise to complete estrogen deficiency. In females this results in virilization in utero and primary amenorrhea with hypergonadotropic hypogonadism at the time of puberty. In men the most striking feature is continued linear bone growth beyond the time of puberty, delayed bone age, and failure of epiphyseal closure, thus indicating an important role of estrogens in bone metabolism in men. In both sexes the symptoms can be alleviated by estrogen administration.
Steroidogenic factor 1 plays multiple roles in endocrine development and function.
Wong M, Ikeda Y, Luo X … +5 more , Caron KM, Weber TJ, Swain A, Schimmer BP, Parker KL
Recent Prog Horm Res · 1997 · PMID 9238852
The nuclear hormone receptor family comprises a group of structurally related transcriptional regulators that mediate the actions of diverse ligands, including steroid hormones, thyroid hormone, vitamin D, and retinoids....
The nuclear hormone receptor family comprises a group of structurally related transcriptional regulators that mediate the actions of diverse ligands, including steroid hormones, thyroid hormone, vitamin D, and retinoids. The nuclear receptor family also contains members for which activating ligands have not been identified-the orphan nuclear receptors. One of these orphan nuclear receptors, steroidogenic factor 1 (SF-1), has emerged as an essential regulator of steroidogenic cell function within the adrenal cortex and gonads; SF-1 also plays important roles in reproduction at all three levels of the hypothalamic-pituitary-gonadal axis. First identified as a tissue-specific regulator of the transcription of the cytochrome P450 steroid hydroxylases, considerably broader roles for SF-1 were revealed by genetic studies in mice lacking SF-1 due to targeted gene disruption. These SF-1-knockout mice had agenesis of their adrenal glands and gonads, male-to-female sex reversal of their internal and external genitalia, impaired gonadotrope function, and agenesis of the ventromedial hypothalamic nucleus. These studies delineated essential roles of SF-1 in regulating endocrine differentiation and function at multiple levels. Despite these insights into roles of SF-1, the precise mechanisms by which SF-1 exerts its multiple effects remain to be determined. This review highlights experiments that have established SF-1 as a pivotal determinant of endocrine differentiation and function and identifies areas in which additional studies are needed to expand our understanding of SF-1 action.
Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action.
Shibata H, Spencer TE, Oñate SA … +4 more , Jenster G, Tsai SY, Tsai MJ, O'Malley BW
Recent Prog Horm Res · 1997 · PMID 9238851
Steroid/thyroid hormone receptors are ligand-dependent transcription factors that regulate diverse aspects of growth, development, and homeostasis by binding as homodimers or heterodimers to their cognate DNA response el...
Steroid/thyroid hormone receptors are ligand-dependent transcription factors that regulate diverse aspects of growth, development, and homeostasis by binding as homodimers or heterodimers to their cognate DNA response elements to modulate transcription of target genes. Transactivation by steroid/ thyroid hormone receptors involves a conserved AF-2 domain located in the distal carboxy-terminus of the receptors. The existence of co-factors, termed co-activators or adapters, was first suggested by transcriptional squelching between progesterone receptors and estrogen receptors. Co-repressors were also postulated to contribute to the silencing function of unliganded thyroid hormone receptor (TR). The yeast two-hybrid system and Far-Western blotting have been used to identify several proteins that interact with members of the steroid/thyroid hormone receptor superfamily in a ligand-sensitive manner. Our laboratory cloned the first functional co-activator, termed steroid receptor co-activator-one (SRC-1), that appears to be a general co-activator for all steroid receptors tested and enhances transactivation of steroid hormone-dependent target genes. Subsequently, many more putative co-activators have been reported, including the SRC-1 related proteins, TIF2 and GRIP1, and other putative and unrelated co-activators such as ARA70, Trip1, RIP140, and TIF1. In addition, another co-activator, CREB-binding protein (CBP), has been shown to enhance steroid receptor-dependent target gene transcription. CBP and SRC-1 interact and synergistically enhance transcriptional activation by the ER and PR. Therefore, a ternary complex-consisting of CBP, SRC-1, and liganded steroid receptors-may form to increase the rate of hormone-responsive gene transcription. Similarly, co-repressors, such as SMRT and N-CoR, for TR and retinoic acid receptors (RAR) have been identified. The unliganded TR and RAR have been shown to inhibit basal promoter activity; this silencing of target gene transcription by unliganded receptors is mediated by these co-repressors. Collectively, available evidence supports the following model of steroid-responsive gene transcription. Upon binding of agonist the receptor changes its conformation in the ligand-binding domain that enables recruitment of co-activators, which allows the receptor to interact with the basal transcriptional machinery more efficiently and to activate transcription. In contrast, binding of antagonists induces a different conformational change in the receptor. Although some antagonist-bound receptor can dimerize and bind to its cognate DNA element, it fails to dislodge the associated co-repressors, which results in a nonproductive interaction with the basal transcriptional machinery. Similarly, the TR and RAR associate with co-repressors in the absence of ligand, thereby resulting in a negative interaction with the transcriptional machinery that silences target gene expression. In the case of mixed agonist/antagonists, such as 4-hydroxytamoxifen, activation of gene transcription may depend on the relative ratio of co-activators and co-repressors in the cell or cell-specific factors that determine the relative agonistic or antagonistic potential of different compounds. These co-activators and co-repressors appear to act as an accelerator and/or a brake that modulates transcriptional regulation of hormone-responsive target gene expression. Thus, the recent discovery of co-activators and co-repressors expands our knowledge of the mechanisms of steroid receptor action.
Coupling signalling pathways to transcriptional control: nuclear factors responsive to cAMP.
Tamai KT, Monaco L, Nantel F … +2 more , Zazopoulos E, Sassone-Corsi P
Recent Prog Horm Res · 1997 · PMID 9238850
Several endocrine and neuronal functions are governed by the cAMP-dependent signalling pathway. In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signalling pathway is mediated by a famil...
Several endocrine and neuronal functions are governed by the cAMP-dependent signalling pathway. In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signalling pathway is mediated by a family of cAMP-responsive nuclear factors. This family consists of a large number of members that may act as activators or repressors. These factors contain the basic domain/ leucine zipper motifs and bind as dimers to cAMP-response elements (CRE). The function of CRE-binding proteins (CREBs) is modulated by phosphorylation by several kinases. Direct activation of gene expression by CREB requires phosphorylation by the cAMP-dependent protein kinase A to the serine-133 residue. Among the repressors, ICER (Inducible cAMP Early Repressor) deserves special mention. ICER is generated from an alternative CREM promoter and constitutes the only inducible cAMP-responsive element binding protein. Furthermore, ICER negatively autoregulates the alternative promoter, thus generating a feedback loop. In contrast to the other members of the CRE-binding protein family, ICER expression is tissue specific and developmentally regulated. The kinetics of ICER expression are characteristic of an early response gene. Our results indicate that CREM plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. We have previously shown that the transcriptional activator CREM is highly expressed in postmeiotic cells. Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes that are under the hormonal control of the hypothalamic-pituitary axis. We have addressed the specific role of CREM in spermiogenesis using CREM-mutant mice generated by homologous recombination. Analysis of the seminiferous epithelium from mutant male mice reveals that spermatogenesis stops at the first step of spermiogenesis. Late spermatids are completely absent, while there is a significant increase in apoptotic germ cells. A series of postmeiotic germ cell-specific genes are not expressed. Mutant male mice completely lack spermatozoa. This phenotype is reminiscent of cases of human infertility. We have shown that ICER is regulated in a circadian manner in the pineal gland, the site of the hormone melatonin production. This night-day oscillation is driven by the endogenous clock (located in the suprachiasmatic nucleus, SCN). The synthesis of melatonin is regulated by a rate-limiting enzyme, the serotonin N-acetyltransferase (NAT). By using the CREM-deficient mice and by analysis of the regulatory region of the gene encoding the serotonin NAT, we have established that ICER is responsible for the amplitude and rhythmicity of NAT and thus for the oscillation in the hormonal synthesis of melatonin.
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