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Mechanism of endoplasmic reticulum retention of mutant vasopressin precursor caused by a signal peptide truncation associated with diabetes insipidus

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第27期274卷 18965-18972页

作者： Beuret, N Rutishauser, J Bider, MD Spiess, M Univ Basel Bioctr CH-4056 Basel Switzerland Kantonsspital Dept Med CH-6000 Luzern 16 Switzerland

Autosomal dominant neurohypophyseal diabetes insipidus is caused by mutations in the gene encoding the vasopressin precursor protein, prepro-vasopressin-neurophysin II. We analyzed the molecular consequences of a mutation (Delta G227) recently identified in a Swiss kindred that destroys the translation initiation codon, In COS-7 cells transfected with the mutant cDNA, translation was found to initiate at an alternative ATG, producing a truncated signal sequence that was functional for targeting and translocation but was not cleaved by signal peptidase, The mutant precursor was completely retained within the endoplasmic reticulum. The uncleaved signal did not affect folding of the neurophysin portion of the precursor, as determined by its protease resistance. However, formation of disulfide-linked aggregates indicated that it interfered with the formation of the disulfide bond in vasopressin, most likely by blocking its insertion into the hormone binding site of neurophysin. Preventing disulfide formation in the vasopressin nonapeptide by mutation of cysteine 6 to serine was shown to be sufficient to cause aggregation and retention. These results indicate that the Delta G227 mutation induces translation of a truncated signal sequence that cannot be cleaved but prevents correct folding and oxidation of vasopressin, thereby causing precursor aggregation and retention in the endoplasmic reticulum.

关键词：氨基酸序列氨基酸取代 COS细胞尿崩症二硫化物类/代谢内质网/代谢鸟苷/代谢分子序列数据诱变定点蛋白质折叠蛋白质前体/遗传学蛋白质前体/代谢蛋白分选信号/代谢血管升压素类/遗传学血管升压素类/代谢动物

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Vasopressin contributes to hyperfiltration, albuminuria, and renal hypertrophy in diabetes mellitus: Study in vasopressin-deficient Brattleboro rats

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第18期96卷 10397-10402页

作者： Bardoux, P Martin, H Ahloulay, M Schmitt, F Bouby, N Trinh-Trang-Tan, MM Bankir, L INSERM U367 F-75005 Paris France Hop Necker Enfants Malad U90 INSERM F-75743 Paris 15 France Hop Necker Enfants Malad Biochim Lab A F-75743 Paris 15 France

Diabetic nephropathy represents a major complication of diabetes mellitus (DM), and the origin of this complication is poorly understood. Vasopressin (VP), which is elevated in type I and type II DM, has been shown to increase glomerular filtration rate in normal rats and to contribute to progression of chronic renal failure in 5/6 nephrectomized rats, The present study was thus designed to evaluate whether VP contributes to the renal disorders of DM, Renal function was compared in Brattleboro rats with diabetes insipidus (DI) lacking VP and in normal Long-Evans (LE) rats, with or without streptozotocin-induced DM, Blood and urine were collected after 2 and 4 weeks of DM, and creatinine clearance, urinary glucose and albumin excretion, and kidney weight were measured. Plasma glucose increased 3-fold in DM rats of both strains, but glucose excretion was approximate to 40% lower in DI-DM than in LE-DM, suggesting less intense metabolic disorders, Creatinine clearance increased significantly in LE-DM (P < 0.01) but failed to increase in DI-DM, Urinary albumin excretion more than doubled in LE-DM but rose by only 34% in DI-DM rats (P < 0.05), Kidney hypertrophy was also less intense in DI-DM than in LE-DM (P < 0.001), These results suggest that VP plays a critical role in diabetic hyperfiltration and albuminuria induced by DM, This hormone thus seems to be an additional risk factor for diabetic nephropathy and, thus, a potential target for prevention and/or therapeutic intervention.

关键词：白蛋白尿肌酸酐/代谢尿崩症/遗传学尿崩症/病理生理学糖尿病实验性/病理生理学糖尿病肾病/病理生理学肾小球滤过率糖尿肥大肾/病理学肾/病理生理学肾功能衰竭慢性/病理生理学肾切除术器官测量大鼠 Brattleboro 大鼠 Long-Evans 血管升压素类/缺乏血管升压素类/遗传学血管升压素类/生理学动物男(雄)性大鼠

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Transgenic studies in rats and mice on the osmotic regulation of vasopressin gene expression

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EXPERIMENTAL PHYSIOLOGY 2000年第Sup1期85卷 211S-222S页

作者： Murphy, D Xu, J Waller, S Univ Bristol Bristol Royal Infirm Dept Med Mol Neuroendocrinol Res Grp Bristol BS2 8HW Avon England Natl Univ Singapore Inst Mol & Cell Biol Neuropeptide Lab Singapore 117609 Singapore

Over the past 10-15 years, profoundly important transgenic techniques have been developed that enable new genes to be introduced into whole mammalian organisms. This review describes the ways in which transgenic animals, both rats and mice, have been used to study the mechanisms by which the expression of the vasopressin gene is confined to specific neurones in the hypothalamus, and how the pattern of that expression is altered following an osmotic challenge to the organism.

关键词：基因表达/生理学下丘脑/生理学小鼠转基因血管升压素类/遗传学水电解质平衡/遗传学动物小鼠大鼠

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Genetic models of vasopressin deficiency

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EXPERIMENTAL PHYSIOLOGY 2000年第Sup1期85卷 203S-209S页

作者： Grant, FD Harvard Univ Brigham & Womens Hosp Sch Med Dept MedEndocrinol Hypertens Div Boston MA 02115 USA

Animal models of genetic hormone deficiency are useful as models for physiological studies of hormone deficiency and hormone action. Structure-function studies of the specific underlying gene defect may help in understanding mechanisms regulating gene expression and secretion of the peptide product. Spontaneous genetic models of vasopressin deficiency, such as the Brattleboro rat and human familial diabetes insipidus, have facilitated many studies of vasopressin. However, the Brattleboro rat may not be an ideal model of genetic vasopressin deficiency and therefore could be less useful for studies of the central nervous system or as a background strain for the introduction of new vasopressin gene constructs. The human model is appropriately Limited by the constraints of human studies, so that engineered animal models of specific diseases, such as familial neurohypophysial diabetes insipidus, are required. The recent development of a vasopressin-null mouse may provide insights into the various roles of vasopressin in the stress response, cardiovascular regulation and behaviour. Additionally, animals with a complete genetic deficiency of vasopressin can serve as a background strain for introduction of novel vasopressin gene constructs to enable sophisticated studies of the regulation of vasopressin expression and the intracellular processes required for appropriate secretion of vasopressin peptide. As advanced techniques of genetic manipulation become more reliable, conditional expression of vasopressin, regulated by time or body site will permit even more detailed studies in this field.

关键词：尿崩症/遗传学尿崩症/病理生理学疾病模型动物小鼠转基因垂体后叶/病理生理学大鼠 Brattleboro 血管升压素类/遗传学动物人类小鼠大鼠

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Quo vadis neurohypophysial hormone research?

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EXPERIMENTAL PHYSIOLOGY 2000年第Sup1期85卷 267S-272S页

作者： Douglas, AJ Ludwig, M Univ Edinburgh Sch Med Dept Biomed Sci Edinburgh EH8 9XD Midlothian Scotland

Here we highlight just a few of the outstanding questions in the field of neurohypophysial hormones that we envisage will be addressed successfully in the new millennium. To begin, we focus on the regulation of receptors. Despite intensive investigation with new drugs, molecular modelling and transgenic models, the determinants of receptor selectivity remain elusive;there may even be more vasopressin or oxytocin receptor subtypes to be discovered. We discuss the controversy over the interesting studies that indicate modulation of oxytocin receptor-binding by steroids. Oxytocin and vasopressin release and action in the brain are discussed from several aspects. Dendritically released oxytocin acting Locally is important for the milk ejection reflex, and similarly released vasopressin is important in regulating patterning of vasopressin neurone activity. Such dendritically released oxytocin and vasopressin is likely to be important in paracrine modulation of neural circuitry involved in neuroendocrine control, and for a range of behaviours. Is it possible that the whole range of behaviours that comprise 'social' (or 'anti-social') or 'maternal' behaviour can be engineered by modifying the expression of just these one or two peptides and their receptors? However, whether gene expression and knockout approaches will answer all the open questions about the real functions of oxytocin and vasopressin remains to be shown.

关键词：小鼠基因敲除分子生物学/发展趋势神经科学/发展趋势催产素/遗传学催产素/代谢垂体后叶/生理学血管升压素类/遗传学血管升压素类/代谢动物人类小鼠

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The role of steroid hormones in the regulation of vasopressin and oxytocin release and mRNA expression in hypothalamo-neurohypophysial explants from the rat

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EXPERIMENTAL PHYSIOLOGY 2000年第Sup1期85卷 171S-177S页

作者： Sladek, CD Swenson, KL Kapoor, R Sidorowicz, HE Chicago Med Sch Dept Physiol N Chicago IL 60064 USA

Vasopressin and oxytocin release from the neural lobe, and the vasopressin and oxytocin mRNA contents of the supraoptic and paraventricular nuclei are increased by hypertonicity of the extracellular fluid. The factors regulating these parameters can be conveniently studied in perifused explants of the hypothalamoneurohypophysial system that include the supraoptic nucleus (but not the paraventricular nucleus) with its axonal projections to the neural Lobe. Vasopressin and oxytocin release and the mRNA content of these explants respond appropriately to increases in the osmolality of the perifusate. This requires synaptic input from the region of the organum vasculosum of the lamina terminalis. Glutamate is a likely candidate for transmitting osmotic information from the organum vasculosum of the lamina terminalis to the magnocellular neurones, because agonists for excitatory amino acid receptors stimulate vasopressin and oxytocin release, and because increased vasopressin release and mRNA content induced in hypothalamo-neurohypophysial explants by a ramp increase in osmolality are blocked by antagonists of both NMDA (N-methyl-D-aspartate) and non-NMDA glutamate receptors. Osmotically stimulated vasopressin release is also blocked by testosterone, dihydrotestosterone, oestradiol and corticosterone. Both oestrogen and dihydrotestosterone block NMDA stimulation of vasopressin release, and in preliminary studies oestradiol blocked AMPA stimulation of vasopressin release. Thus, steroid inhibition of osmotically stimulated vasopressin secretion may reflect inhibition of mechanisms mediated by excitatory amino acids. Recent studies have demonstrated numerous mechanisms by which steroid hormones may impact upon neuronal function. Therefore, additional work is warranted to understand these effects of the steroid hormones on vasopressin and oxytocin secretion and to elucidate the potential contribution of these mechanisms to regulation of hormone release in vivo.

关键词：细胞培养的基因表达/生理学谷氨酸/生理学性腺甾类激素/生理学下丘脑-垂体系统/细胞学下丘脑-垂体系统/生理学催产素/遗传学催产素/代谢 RNA 信使/代谢血管升压素类/遗传学血管升压素类/代谢动物大鼠

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Gene expression in the forebrain of dexamethasone-treated pigs: effects on stress neuropeptides in the hypothalamus and hippocampus and glutamate receptor subunits in the hippocampus

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RESEARCH IN VETERINARY SCIENCE 2000年第1期69卷 25-31页

作者： Vellucci, SV Parrott, RF MAFF Welf & Behav Lab Dept Neurobiol Babraham Inst Cambridge CB2 4AT England

Gene expression studies advance our understanding of the effects of stress and glucocorticoids on brain function and give a new direction to animal welfare research. In this context, the presence of messenger RNAs (mRNAs) for corticotrophin releasing hormone (CRH) and vasopressin (vp) in the porcine hypothalamus has recently been documented. This study investigated the expression of CRH, vr and ionotropic glutamate receptor (iGluR) subunit mRNAS in the brains of pigs treated with the synthetic glucocorticoid dexamethasone (Dex 5 mg kg(-1) i.v.). In the hypothalamus, VP, but not CRH, mRNA was reduced 3 hours after Dex. In the hippocampus, expression of mRNAs for some iGluR subunits appeared to he differentially regulated 6 hours after Dex. In addition, CRH message was detected in the hippocampus and significantly upregulated in the CA1 region 3 hours after Dex. The relevance of these findings to stress neurobiology of the growing, pig is discussed. (C) 2000 Harcourt Publishers Ltd.

关键词：促肾上腺皮质素释放激素/生物合成促肾上腺皮质素释放激素/化学促肾上腺皮质素释放激素/遗传学 DNA探针/化学地塞米松/药理学基因表达调控/药物作用糖皮质激素类/药理学海马/药物作用海马/代谢下丘脑/药物作用下丘脑/代谢图像处理计算机辅助原位杂交/兽医学 RNA 信使/生物合成受体 AMPA/生物合成受体 AMPA/化学受体 AMPA/遗传学受体 N-甲基-D-天冬氨酸/生物合成受体 N-甲基-D-天冬氨酸/化学受体 N-甲基-D-天冬氨酸/遗传学应激/代谢应激/兽医学猪/生理学血管升压素类/生物合成血管升压素类/化学血管升压素类/遗传学动物男(雄)性

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Differential regulation of corticotropin-releasing hormone and vasopressin transcription by glucocorticoids

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ENDOCRINOLOGY 1999年第12期140卷 5642-5650页

作者： Ma, XM Aguilera, G NICHHD Sect Endocrine Physiol DEB NIH Bethesda MD 20892 USA

CRH and vasopressin (VP), the main regulators of pituitary ACTH secretion, co-exist in parvocellular cells of the PVN, but their levels of expression are regulated differentially during manipulations of the hypothalamic pituitary adrenal (HPA) axis. The effects of glucocorticoids on this system was studied using in situ hybridization with intronic and exonic probes to measure changes in CRH and VP messenger RNA (mRNA) and heteronuclear (hn) RNA in 48-h adrenalectomized (ADX) rats receiving injections of corticosterone (2.8 mg/ 100 g, ip) or vehicle. We also determined the time course of changes in VP expression following the first 12 h of ADX Levels of VP heteronuclear Om) RNA and the number of parvocellular cells containing VP hnRNA remained very low in sham operated rats, whereas biphasic changes were observed after ADX. Grain density levels increased 11.5-fold over sham-operated controls by 6 h, declined to 2-fold by 18 h, to increase again to 10- and 20-fold by 48 and 72 h, respectively. In 48-h ADX rats, vehicle injection increased CRH hnRNA levels transiently (11-fold the basal by 15 and 30 min), returning to basal at 60 min, whereas VP hnRNA levels increased progressively up to 28-fold the basal by 2 h. Corticosterone injection had no significant effect on vehicle-induced increases in CRH hnRNA, in spite of marked elevations in circulating corticosterone. In contrast to CRH;VP hnRNA levels increased only transiently by 15 min, and then decreased below basal (near sham-ADX levels) by 2 h. The data show that in normal conditions the responsiveness of parvocellular neurons to stress is under marked inhibition by the low resting levels of glucocorticoids, and that the sensitivity of CRH and VP transcription to glucocorticoid feedback is markedly different.

关键词：肾上腺切除术皮质酮/血液皮质酮/药理学促肾上腺皮质素释放激素/遗传学基因表达调控/药物作用糖皮质激素类/药理学原位杂交动力学 RNA 核不均一/分析 RNA 信使/分析大鼠 Sprague-Dawley 转录遗传/药物作用血管升压素类/遗传学动物男(雄)性大鼠

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