Evidence for a Precursor in Vasopressin Biosynthesis

Sachs, Hans; Takabatake, Yutaka

doi:10.1210/endo-75-6-943

Cited by 222 publications

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“…The oxytocin, vasopressin, and neurophysins are transported, in axons of the neurons that synthesize them, to the posterior pituitary via the median eminence. Sachs and his colleagues (4)(5)(6)(7)(8) have hypothesized that vasopressin and its neurophysin come from a common precursor protein that is synthesized in the hypothalamus by a ribosomal mechanism. We have already presented some evidence consistent with this hypothesis (9,10 sopressin and its associated neurophysin (11,12) and hence have diabetes insipidus-to determine which of the putative precursors, intermediates, and neurophysins are related to vasopressin and which to oxytocin.…”

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confidence: 99%

Neurophysin biosynthesis in normal rats and in rats with hereditary diabetes insipidus.

Brownstein¹,

Gainer²

1977

Proc. Natl. Acad. Sci. U.S.A.

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When [35S]cysteine was injected adjacent to the supraoptic nucleus (SON) in rats, it was rapidly incorporated into proteins in the SON. The [35S]cysteine-labeled proteins extracted from the SON were separated by isoelectric focusing on polyacrylamide gels. Twenty minutes after the injection of [I Scysteine, two major labeled peaks (pI = 5.4 and 6.1) were found in the SON of normal rats; Brattleboro rats had only one major labeled peak (pI = 5.4). One hour after the injection, four major radioactive peaks were found in the SON of normal animals (pI = 5.1,5.4,5.6, and 6.1). Animals with diabetes insipidus had only two major labeled proteins (pl = 5.1 and 5.4). Twenty-four hours after normal rats were injected with l35S-cysteine, all of the labeled peaks described above, except for the one with pI = 5. Neurons in the supraoptic nucleus (SON) and paraventricular nucleus synthesize two peptide hormones (oxytocin and vasopressin) as well as their "carrier" proteins (neurophysins) (1-3). The oxytocin, vasopressin, and neurophysins are transported, in axons of the neurons that synthesize them, to the posterior pituitary via the median eminence. Sachs and his colleagues (4-8) have hypothesized that vasopressin and its neurophysin come from a common precursor protein that is synthesized in the hypothalamus by a ribosomal mechanism. We have already presented some evidence consistent with this hypothesis (9, 10).We have found that, within 1 hr, [a3S]cysteine injected adjacent to the SON is incorporated into two proteins with molecular weights (Mr) of about 20,000 and pI of 5.4 and 6.1 (9, 10). It appears that, in time, these two proteins give rise to the two neurophysins (Mr 12,000). sopressin and its associated neurophysin (11, 12) and hence have diabetes insipidus-to determine which of the putative precursors, intermediates, and neurophysins are related to vasopressin and which to oxytocin. MATERIALS AND METHODS Animals and Operative Procedures. Female OsborneMendel (225-250 g) and Brattleboro (130-150 g) rats were used in these studies. Some of the normal Osborne-Mendel rats were given 2% (wt/vol) saline to drink for 1 week prior to use in order to stimulate vasopressin and neurophysin synthesis; others were given water ad lib as were the Brattleboro animals.The animals were anesthetized with ether, their heads were fixed in a stereotaxic device (50, nose down), and a flap of bone was removed from their skulls. The 30-gauge stainless steel needles were positioned 7 mm rostral to the interauricular line (6.8 mm for Brattleboro rats), and 2.5 mm on each side of the midline (2 mm for Brattleboro animals). The needles were lowered 8.6 mm (8.2 mm for Brattleboro animals) beneath the dural surface, and 1 ,ul of a solution containing 20,Ci of I35S]cysteine (50 Ci/mmol; New England Nuclear) in 0.9% NaCl and 10 mM dithiothreitol was injected through each needle over a 4-min period. After the injection, the needles were left in place for 10 min and then removed. At various times after the injections the rats were killed by...

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confidence: 99%

Neurophysin biosynthesis in normal rats and in rats with hereditary diabetes insipidus.

Brownstein¹,

Gainer²

1977

Proc. Natl. Acad. Sci. U.S.A.

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“…In 1964, Howard Sachs had produced suggestive evidence for a precursor of vasopressin, but it proved difficult to isolate and identify (37). Meanwhile, precursors for other bioactive peptides completely lacking the exacting assembly requirements of the insulin molecule began to be identified in the early 1970s, including proparathyroid hormone (John Potts and co-workers), proglucagon (Howard Tager), and promelanocyte-stimulating hormone/ACTH/endorphin or proopiomelanocortin (POMC) (Elizabeth Eipper and Richard Mains) (38).…”

Section: Reflections: Adventures With Insulin In the Islets Of Langermentioning

confidence: 99%

Adventures with Insulin in the Islets of Langerhans

Steiner

2011

Journal of Biological Chemistry

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Insulin is a small but beautifully organized protein with a unique two-chain structure, the first protein to be sequenced. The mechanism of its biosynthesis invited much initial speculation but was finally clarified by the discovery of proinsulin, its single-chain precursor. The rich present-day field of protein precursor processing via post-translational proteolysis within the secretory pathway arose in the early 1970s as an offshoot of studies on insulin biosynthesis, which provided a novel paradigm for the generation of many other small neuroendocrine peptides. Before long, this mechanism was also found to play a role in the production of a much wider spectrum of proteins traversing the secretory pathway (receptors, growth factors, blood-clotting components, and even many viral envelope proteins) occurring in almost all eukaryotic cells. Indeed, yeast provided a key clue in the search for the proprotein convertases, the endoproteases that work along with carboxypeptidases and other modifying enzymes, such as the amidating enzyme complex (PAM), in converting inactive or less active precursor proteins into their fully active peptide products. In this "Reflections" article, I have tried to recount the people and events in my life that led to my involvement first in basic biochemical research and then on to insulin, proinsulin, and many relevant related areas that continue to fascinate and challenge my colleagues and me, as well as many other biomedical scientists today, as diabetes mellitus increasingly threatens human health throughout our contemporary world.

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“…Verney reported in 1947 that the release of antidiuretic hormone was controlled by central osmoreceptors, located in or near the supraoptic nucleus, and by 1951 Bargmann and Scharrer had established that the hormones of the posterior pituitary were produced by cells in the hypothalamus (Bargmann, 1966). This led to finding with electron microscopy that the hormones are stored within dense core vesicles (Palay, 1955), and to the demonstration of the synthesis of the peptides in the magnocellular cell bodies and their axonal transport to form and replenish the store in the posterior pituitary (Sachs & Takabatake, 1964). The electrical stimulation studies by Harris in the late 1940s (Harris, 1955), showing that depolarisation of the axon terminals in the neurohypophysis would release the hormones, made clear that the signal to release the peptides from the posterior pituitary was conveyed from the hypothalamus on a dramatically faster timescale than the transport of the peptides.…”

Section: Foundations -The First Fifty Yearsmentioning

confidence: 99%

Veni, vidi, vici: the neurohypophysis in the twentieth century

Russell

Leng

2000

Experimental Physiology

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We outline the key discoveries in the first 70 years of research on the neurohypophysis that provided the foundations for more recent studies in the last 30 years. We consider the extent to which these recent studies, which have exploited molecular technologies, cellular electrophysiological techniques and mechanistic behavioural investigations, have advanced or changed our understanding of the functions of oxytocin and vasopressin. The different evolutionary pressures on the oxytocin and vasopressin systems are discussed. Lastly, we focus on the mechanisms underlying the burst-firing activity of oxytocin neurones in lactation as a problem not yet solved, and probably requiring a presently improbable conceptual leap to understand. Experimental Physiology (2000) 85S, IS-6s.

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Evidence for a Precursor in Vasopressin Biosynthesis

Cited by 222 publications

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Neurophysin biosynthesis in normal rats and in rats with hereditary diabetes insipidus.

Neurophysin biosynthesis in normal rats and in rats with hereditary diabetes insipidus.

Adventures with Insulin in the Islets of Langerhans

Veni, vidi, vici: the neurohypophysis in the twentieth century

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