A form of water with properties very different from those well established for water has been reported in a series of papers by Deryagin and coworkers (1). Water in this unusual state has been called "anomalous water" by this group to distinguish it from ordinary water. It has been prepared in two ways. As described by Fedyakin (2), secondary columns were observed growing near both ends of a column of water sealed in a glass capillary 2 to 4 ,tm in diameter. In subsequent work, the anomalous water was prepared by the condensation of water vapor in glass and fused quartz capillaries at relative pressures somewhat less than unity (3). Some of the reported properties of this water are (i) low vapor pressure; (ii) solidification at -40°C or lower temperatures to a glass-like
A peptide has been isolated from ovine hypothalamus which, at 1 x 10(-9)M, inhibits secretion in vitro of immunoreactive rat or human growth hormones and is similarly active in vivo in rats. Its structure is H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH The synthetic replicate is biologically active.
Corticotropin-releasing factor (CRF), a peptide first isolated from mammalian brain, is critical in the regulation of the pituitary-adrenal axis, and in complementary stress-related endocrine, autonomic and behavioural responses. Fish urotensin I and amphibian sauvagine were considered to be homologues of CRF until peptides even more closely related to CRF were identified in these same vertebrate classes. We have characterized another mammalian member of the CRF family and have localized its urotensin-like immunoreactivity to, and cloned related complementary DNAs from, a discrete rat midbrain region. The deduced protein encodes a peptide that we name urocortin, which is related to urotensin (63% sequence identity) and CRF (45% sequence identity). Synthetic urocortin evokes secretion of adrenocorticotropic hormone (ACTH) both in vitro and in vivo and binds and activates transfected type-1 CRF receptors, the subtype expressed by pituitary corticotropes. The coincidence of urotensin-like immunoreactivity with type-2 CRF receptors in brain, and our observation that urocortin is more potent than CRF at binding and activating type-2 CRF receptors, as well as at inducing c-Fos (an index of cellular activation) in regions enriched in type-2 CRF receptors, indicate that this new peptide could be an endogenous ligand for type-2 CRF receptors.
Since corticotropin-releasing factor (CRF) was first characterized, a growing family of ligands and receptors has evolved. The mammalian family members include CRF, urocortinI (UcnI), UcnII, and UcnIII, along with two receptors, CRFR1 and CRFR2, and a CRF binding protein. These family members differ in their tissue distribution and pharmacology. Studies have provided evidence supporting an important role of this family in regulation of the endocrine and behavioral responses to stress. Although CRF appears to play a stimulatory role in stress responsivity through activation of CRFR1, specific actions of UcnII and UcnIII on CRFR2 may be important for dampening stress sensitivity. As the only ligand with high affinity for both receptors, UcnI's role may be promiscuous. Regulation of the relative contribution of the two CRF receptors to brain CRF pathways may be essential in coordinating physiological responses to stress. The development of disorders related to heightened stress sensitivity and dysregulation of stress-coping mechanisms appears to involve regulatory mechanisms of CRF family members.
Amyloids are highly organized cross β-sheet-rich protein or peptide aggregates that are associated with pathological conditions including Alzheimer's disease and type II diabetes. However, amyloids may also have a normal biological function as demonstrated by fungal prions, which are involved in prion replication, and the amyloid protein Pmel17, which is involved in mammalian skin pigmentation. Here, we show that peptide and protein hormones in secretory granules of the endocrine system are stored in an amyloid-like cross β-sheet-rich conformation. Thus, in contrast to the original association of amyloids with diseases, functional amyloids in the pituitary and other organs can contribute to normal cell and tissue physiology.Cells transport newly synthesized secretory proteins and peptides in vesicles via the endoplasmic reticulum (ER) and Golgi for release into the extracellular space (1,2). Some secretory cells, such as neuroendocrine cells and exocrine cells, store secretory proteins and peptides for extended time periods in a highly concentrated form in membrane-enclosed electron-dense cores termed "secretory granules" (1,3,4), which are derived from the Golgi complex. The dense cores of these granules are made up of large, insoluble secretory protein and peptide aggregates that are formed by self-association (4-6). The granules are not amorphous, but possess a distinct molecular organization, possibly of crystalline structures (7) or large intermolecular aggregates (5,8).Amyloid fibrils are cross-β-sheet structures that are primarily associated with several neurodegenerative diseases including Alzheimer's disease. However, amyloid fibril formation also provides biologically functional entities termed functional amyloids (9) and are present in Escherichia coli (10), silkworm (11), fungi (12), and mammalian skin (13). The cross-β-sheet motif is composed of intermolecular β-sheets along the fibril axis with the β-strands aligned perpendicularly to the fibril axis. An amyloid-like structure of peptide and protein hormones in secretory granules could explain most of their properties.To address the question whether peptide and protein hormones are stored in secretory granules in an amyloid-like aggregation state, we first asked if a diverse set of peptide and protein hormones could form amyloids in vitro at granule-relevant pH 5.5. 42 peptide and protein hormones from multiple species and organs were selected randomly, some linear and some cyclic, with a variety of different three dimensional structures (Table S2). This set of hormones was assayed for a capacity to form amyloids by the amyloid-specific dyes thioflavin T (Thio T), congo red (CR), luminescent conjugated polyelectrolyte probes (LCP), by the conformational transition into β-sheet-rich structure measured by circular dichroism (CD), and by the presence of fibrils in electron microscopy (EM) images. Furthermore, x-ray fiber diffraction was measured for a subset of hormones (Table S1). Only 10 hormones out of the 42 showed significant formation of...
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