Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial hypothalamic diabetes insipidus is an autosomal dominant disorder characterized by deficient vasopressin synthesis. Different point mutations in the vasopressin-neurophysin (VP-NP) precursor gene have been found in affected families. In a Dutch kindred, a single G to T transversion in the NP-encoding exon B of one allele converts the highly conserved glycine 17 to a valine residue. In order to examine whether this point mutation affects the processing and transport of the VP-NP precursor, the normal (HV2) and mutant (MT6) vasopressin cDNAs were stably expressed in the mouse pituitary cell line AtT20. The normal precursor was correctly glycosylated and processed, and NP was detected in the culture medium. Secretion of NP was stimulated by 8-bromo-cAMP, indicating that the normal precursor was targeted to the regulated secretory pathway. In contrast, the mutant precursor was synthesized, but processing and secretion were dramatically reduced. The mutant precursor was core-glycosylated but remained endoglycosidase H-sensitive, suggesting that the protein did not reach the trans-Golgi network. These results were supported by immunocytochemical studies. In HV2 cells, NP derived from the precursor was concentrated in the tips of the cell processes where secretory granules accumulate. In MT6 cells, NP staining was restricted to the endoplasmic reticulum (ER) as determined by colocalization with an ER-resident protein, BiP. These results suggest that the mutation within the conserved part of NP alters the conformation of the precursor and thus triggers its retention in the ER.
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PMID:Heterologous expression of human vasopressin-neurophysin precursors in a pituitary cell line: defective transport of a mutant protein from patients with familial diabetes insipidus. 894 33

Platelet-derived growth factor (PDGF) is established to function importantly in the growth, development, and function of most cardiovascular tissues. However, evidence that the factor participates directly in the growth and development of the mammalian myocardium is lacking. H9c2 rat embryonic ventricular myocytes were found to respond to PDGF-BB with a rapid mobilization of cell-associated Ca2+ and increased rates of protein synthesis, followed by markedly increased rates of DNA synthesis. PDGF acted as a full mitogen for these myocytes. Evidence is provided that documents the expression of classical PDGF-beta, but not PDGF-alpha, receptors in H9c2 cells. Scatchard analysis revealed the presence of 44,000 beta-receptors per myocyte. Cell shortening and clustering of plasmalemmal beta-receptors occurred within 30 min of exposure to PDGF-BB. Treatment was also associated with a transient increase in the rate of synthesis of GRP78/BiP, consistent with a transitory release of Ca2+ from the sarcoplasmic/endoplasmic reticulum [S(E)R]. Increased rates of protein synthesis at early times of PDGF treatment were additive with those occurring in response to arginine vasopressin, indicating different mechanisms of translational upregulation by these agents. The mitogenic effects of PDGF were delayed by vasopressin, which causes H9c2 myocytes to undergo hypertrophy while promoting the persistent depletion of S(E)R Ca2+ stores. In the presence of PDGF, vasopressin did not induce hypertrophy. As compared to untreated myocytes, DNA synthesis in PDGF-treated myocytes was optimized at lower extracellular Ca2+ concentrations and was significantly less sensitive to inhibition by ionomycin. H9c2 cells appear to provide a useful embryonic cardiomyocyte model in which to examine both PDGF-activated proliferative and vasopressin-activated hypertrophic events and the importance of transient vs. sustained Ca2+ release in these events.
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PMID:Functional receptor for platelet-derived growth factor in rat embryonic heart-derived myocytes: role of sequestered Ca2+ stores in receptor signaling and antagonism by arginine vasopressin. 1183 99

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) precursor. The pathogenesis of FNDI is proposed to involve mutant protein-induced loss of AVP-producing neurons. We established murine knock-in models of two different naturally occurring human mutations that cause FNDI. A mutation in the AVP signal sequence [A(-1)T] is associated with a relatively mild phenotype or delayed presentation in humans. This mutation caused no apparent phenotype in mice. In contrast, heterozygous mice expressing a mutation that truncates the AVP precursor (C67X) exhibited polyuria and polydipsia by 2 months of age and these features of DI progressively worsened with age. Studies of the paraventricular and supraoptic nuclei revealed induction of the chaperone protein BiP and progressive loss of AVP-producing neurons relative to oxytocin-producing neurons. In addition, Avp gene products were not detected in the neuronal projections, suggesting retention of WT and mutant AVP precursors within the cell bodies. In summary, this murine model of FNDI recapitulates many features of the human disorder and demonstrates that expression of the mutant AVP precursor leads to progressive neuronal cell loss.
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PMID:A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons. 1466 Jul 40

Low sensitivity is characteristic of many proteomics methods. Presented here is an approach that combines proteomics based on difference gel electrophoresis (DIGE) with bioinformatic pathways analysis to identify both abundant and relatively nonabundant proteins in inner medullary collecting duct (IMCD) altered in abundance during escape from vasopressin-induced antidiuresis. Rats received the vasopressin analog dDAVP by osmotic minipump plus either a daily water load (vasopressin escape) or only enough water to replace losses (control). Immunoblotting confirmed the hallmark of vasopressin escape, a decrease in aquaporin-2, and demonstrated a decrease in the abundance of the urea transporter UT-A3. DIGE identified 22 mostly high-abundance proteins regulated during vasopressin escape. These proteins were analyzed using pathways analysis software to reveal protein clusters incorporating the proteins identified by DIGE. A single dominant cluster emerged that included many relatively low-abundance proteins (abundances too low for DIGE identification), including several transcription factors. Immunoblotting confirmed a decrease in total and phosphorylated c-myc, a decrease in c-fos, and increases in c-jun and p53. Furthermore, immunoblotting confirmed hypothesized changes in other proteins in the proposed network: Increases in c-src, receptor for activated C kinase 1, calreticulin, and caspase 3 and decreases in steroid receptor co-activator 1, Grp78/BiP, and annexin A4. This combined approach proved capable of uncovering regulatory proteins that are altered in response to a specific physiologic perturbation without being detected directly by DIGE. The results demonstrate a dominant protein regulatory network in IMCD cells that is altered in association with vasopressin escape, providing a new framework for further studies of signaling in IMCD.
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PMID:Combined proteomics and pathways analysis of collecting duct reveals a protein regulatory network activated in vasopressin escape. 1607 66

The immunoglobulin heavy chain binding protein (BiP) is an endoplasmic reticulum (ER) chaperone that facilitates the proper folding of newly synthesized secretory and transmembrane proteins. Here we report that BiP mRNA was expressed in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in wild-type mice under basal conditions. Dual in situ hybridization in the SON and PVN demonstrated that BiP mRNA was expressed in almost all the neurons of arginine vasopressin (AVP), an antidiuretic hormone. BiP mRNA expression levels were increased in proportion to AVP mRNA expression in the SON and PVN under dehydration. These data suggest that BiP is involved in the homeostasis of ER function in the AVP neurons in the SON and PVN.
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PMID:BiP mRNA expression is upregulated by dehydration in vasopressin neurons in the hypothalamus in mice. 2223 May 48

Arginine-vasopressin (AVP) is a peptide hormone normally secreted from neuroendocrine cells via the regulated secretory pathway. In Familial Neurohypophyseal Diabetes Insipidus (FNDI), an autosomal dominant form of central diabetes insipidus, mutations of pro-vasopressin appear to accumulate in the endoplasmic reticulum (ER) causing a lack of biologically active AVP in the blood. To investigate the effect of pro-vasopressin mutations regarding intracellular functions of protein targeting and secretion, we created two FNDI-associated amino acid substitution mutants, e.g., G14R, and G17V in frame with green fluorescent protein (GFP) and pro-vasopressin (VP) in frame with red fluorescent protein (VP-RFP). Fluorescence microscopy of Neuro-2a cells expressing these constructs revealed co-localization of VP-GFP and VP-RFP to punctate granules along the length and accumulating at the tips of neurites, characteristic of regulated secretory granules. In contrast, the two FNDI-associated amino acid substitution mutants, e.g., G14R-GFP, and G17VGFP, were localized to a perinuclear region of the Neuro-2a cells characteristic of the endoplasmic reticulum. Co-expression of these mutants with VP-RFP showed VP-RFP was retained in the ER, co-localized with the mutants suggesting the formation of heterodimers as found in FNDI. Stimulated secretion experiments indicated that VP-GFP was secreted in an inducible manner whereas, G14R-GFP and G17V-GFP were retained to nearly 100% within the cells. Analysis by western blotting and semi-quantitative RT-PCR indicated an increased protein and mRNA expression for an ER resident molecular chaperone, BiP. Further analysis of ER-storage disease-associated proteins such as caspase 12 and CHOP showed an increase in these as well. The results suggest that G14R-GFP and G17V-GFP are retained in the ER of Neuro-2a cells, resulting in up-regulation of the molecular chaperone BiP, and activation of the ER-storage disease-associated caspase cascade system.
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PMID:Misfolding of Mutated Vasopressin Causes ER-Retention and Activation of ER-Stress Markers in Neuro-2a Cells. 2456 68