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U.C.T./M.R.C. Protein Research Unit, Department of Chemical Pathology, Medical School, Observatory 7925, Cape Town, Republic of South Africa
(Received 26 January 1978)
Higher molecular weight (HMW) immunoreactive forms of somatostatin have been reported in extracts of ovine hypothalami (Vale, Ling, Rivier, Villarreal, Rivier, Douglas & Brown, 1976), rat pancreas and stomach (Arimura, Sato, Dupont, Nishi & Schally, 1975) and human pancreatic somatostatinoma (Larsson, Hirsch, Holst, Ingemansson, Kühl, Jensen, Lundquist & Rehfeld, 1977). However, the possibility that the HMW immunoreactive substances were oligomers of somatostatin or somatostatin bound to larger molecules was not excluded. The present study was undertaken to establish that authentic HMW immunoreactive somatostatin is present in the ovine hypothalamus and to glean information on the structural relationship of the HMW species with somatostatin.
Sheep hypothalami were extracted and subjected to gel permeation chromatography as described previously by Millar, Aehnelt & Rossier (1977). Fractions were assayed for somatostatin immunoreactivity
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ABSTRACT
Passive immunization of immature chickens with sheep somatostatin (SRIF) antiserum promptly increased the basal plasma GH concentration and augmented TRH-induced GH secretion. Although exogenous SRIF had no inhibitory effect on the basal GH concentration in untreated birds or birds pretreated with non-immune sheep serum, it suppressed the stimulatory effect of SRIF immunoneutralization on GH secretion. These results suggest that SRIF is physiologically involved in the control of GH secretion in birds, in which it appears to inhibit GH release tonically.
J. Endocr. (1986) 111, 91–97
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Introduction
The two naturally occurring bioactive peptides, somatostatin (SRIF)-14 and SRIF-28 are physiological regulators of pituitary growth hormone (GH), pancreatic endocrine secretions, and gastrointestinal motility and hormone secretion (Brazeau et al. 1972, Mandarino et al. 1981). These biological effects are mediated through specific high-affinity G-protein-coupled receptors containing seven transmembrane domains. Five distinct SRIF receptor (SSTR) subtypes are located on different chromosomes (Bruno et al. 1992, Yasuda et al. 1992, Roher et al. 1993, Xu et al. 1993, Yamada et al. 1992a,b, 1993), and consist of 364–418-amino acid proteins (39–46 kDa) which display 42–60% identity among the different subtypes and 81–97% homology with rodent receptors (Reisine & Bell 1995). The SSTRs interact with different G-proteins (Rens-Domiano et al. 1992, Law et al. 1993) to inhibit adenylate cyclase activity. Receptor subtypes are also associated with other signal-transduction mechanisms, including cationic channel conductance reduction and tyrosine phosphatase activation (Reisine & Bell
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Departments of Pathology, Medicine, and Physiology and Biophysics, School of Medicine, University of Washington, Seattle, Washington 98195, U.S.A.
(Received 1 September 1976)
Somatostatin (somatotrophin release inhibiting factor) antagonizes the secretion of somatotrophin (Brazeau, Vale, Burgus, Ling, Butcher, Rivier & Guillemin, 1973), insulin (Alberti, Christensen, Christensen, Hansen, Iversen, Lundbaeck, Seyer-Hansen & Orskov, 1973), thyrotrophin (Hall, Besser, Schally, Coy, Evered, Goldie, Kastin, McNeilly,Mortimer,Phenekos, Tunbridge & Weightman, 1973), glucagon (Iversen, 1974; Koerker, Ruch, Chideckel, Palmer, Goodner, Ensinck & Gale, 1974; Mortimer, Tunbridge, Carr, Yeomans, Lind, Coy, Bloom, Kastin, Mallinson, Besser, Schally & Hall, 1974), gastrin (Bloom, Mortimer, Thorner, Besser, Hall, Gomez-Pan, Roy, Russell, Coy, Kastin & Schally, 1974), gastric acid (Barros D'Sa, Bloom & Baron, 1975; Gomez-Pan, Reed, Albinus, Shaw, Hall, Besser, Coy, Kastin & Schally, 1975) and pepsin (Gomez-Pan et al. 1975) but appears to have no effect on secretion of follicle-stimulating hormone, luteinizing hormone, prolactin, corticotrophin, corticosteroids (Hall et al. 1973),
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Immunoreactive somatostatin is present in the brain, gut and pancreas of the South African clawed toad, but is absent from the skin, a rich source of many other brain–gut peptides.
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Recent studies in animals have demonstrated that growth hormone (GH) secretion is controlled by GH releasing factor (GHRF) and GH inhibiting factor (somatostatin). Somatostatin has not only been purified from the ovine hypothalamus, but also synthesized (Brazeau, Vale, Burgus, Ling, Butcher, Rivier & Guillemin, 1973). It has been demonstrated recently that synthetic somatostatin suppresses the spontaneous secretion of GH and the increase in plasma GH induced by i.v. injection of pentobarbitone in the rat (Brazeau, Rivier, Vale & Guillemin, 1974). We have previously reported that a single i.v. injection of isoprenaline or chlorpromazine causes a significant increase in plasma GH in the rat (Kato, Dupre & Beck, 1973). In the present experiment, we examined the effect of synthetic somatostatin (kindly supplied by Dr N. Yanaihara) on the response of plasma GH to isoprenaline or chlorpromazine in rats.
Wistar strain male rats, weighing 180–220 g, were housed in an air-conditioned room
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ABSTRACT
Atrophy of the exocrine pancreas was induced in rabbits by pancreatic duct ligation. Somatostatin concentration and binding in cytosol from rabbit duodenal mucosa were studied after 6 and 14 weeks of pancreatic duct ligation. Somatostatin-like immunoreactivity was significantly increased in the duodenal mucosa in both periods. Scatchard analysis showed a parallel increase in the number of binding sites rather than a change in their affinity. The physiological significance of these findings remains to be clarified.
J. Endocr. (1988) 118, 227–232
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ABSTRACT
The presence of multiple forms of somatostatin-like immunoreactivity (SSLI) in the rat hypothalamus was confirmed using a sensitive radioimmunoassay in conjunction with gel filtration chromatography and high performance liquid chromatography (HPLC). Gel filtration chromatography of hypothalamic extracts revealed the presence of four forms of SSLI with estimated molecular weights of 1500, 3000, 6000 and 10000. Analysis by HPLC indicated that the 1500 and 3000 mol. wt forms of SSLI corresponded respectively to somatostatin-14 (SS14) and somatostatin-28 (SS28) whereas the 6000 and 10 000 mol. wt forms eluted together as a composite peak of high molecular weight somatostatin (HMW-SS). The proportions of SS14 (63%), SS28 (12%) and HMW-SS (25%) present in the hypothalamus were similar to those in the amygdala (59, 9 and 32% respectively). In contrast, the median eminence contained a greater proportion of SS28 than the other tissues: SS14, SS28 and HMW-SS were present in the proportions 40:24:26%. These results show that the rat median eminence differs from the hypothalamus as a whole in containing SS14 and SS28 in almost equimolar concentrations. The localized abundance of SS28 in the nerve terminals of the median eminence suggests a specific role for this peptide in the hypothalamic regulation of growth hormone secretion.
J. Endocr. (1985) 105, 383–389
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
UVA Health System Charlottesville, Virginia, USA
Lawson Health Research Institute, London, Ontario, Canada
Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, Oregon, USA
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Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
UVA Health System Charlottesville, Virginia, USA
Lawson Health Research Institute, London, Ontario, Canada
Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, Oregon, USA
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Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
UVA Health System Charlottesville, Virginia, USA
Lawson Health Research Institute, London, Ontario, Canada
Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, Oregon, USA
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Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
UVA Health System Charlottesville, Virginia, USA
Lawson Health Research Institute, London, Ontario, Canada
Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, Oregon, USA
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Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
UVA Health System Charlottesville, Virginia, USA
Lawson Health Research Institute, London, Ontario, Canada
Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, Oregon, USA
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Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
UVA Health System Charlottesville, Virginia, USA
Lawson Health Research Institute, London, Ontario, Canada
Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, Oregon, USA
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Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
UVA Health System Charlottesville, Virginia, USA
Lawson Health Research Institute, London, Ontario, Canada
Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, Oregon, USA
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Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
UVA Health System Charlottesville, Virginia, USA
Lawson Health Research Institute, London, Ontario, Canada
Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, Oregon, USA
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during the first month of life ( Diaz-Torga et al. 2002 ), predicts impaired somatotrope cell number and function in the adult pituitary. We compared somatotrope cell number and in vitro responsiveness with GHRH, somatostatin (ST), and ghrelin in
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ABSTRACT
The effect of somatostatin on GH-releasing factor (GRF)-induced desensitization of somatotrophs was studied in vitro. Primary cultures of rat anterior pituitary cells pretreated for 4 or 18 h with GRF(1–40) (100 nmol/l) showed a 50% or greater reduction in maximal GH release when rechallenged with 10 nmol GRF/l. Rechallenge GRF dose–response curves were either very flat, making accurate measurement of the dose giving 50% maximum stimulation (ED50) impossible, or the ED50 concentration was increased from 0·3 nmol/l (untreated) to 2 nmol/l (GRF pretreated). Although GRF pretreatment reduced cellular GH content by 40–50%, correction for this did not restore GRF responsiveness measured in terms of maximal GRF-stimulated/unstimulated GH release (maximal/basal ratio), or the GRF ED50 concentration. Maximal/basal GH release per 4 h from GRF-pretreated cells was reduced when cells were rechallenged with forskolin (5 μmol/l) or calcium ionophore (A23187; 10 μmol/l), to the same extent as when rechallenged with 10 nmol GRF/l. Although this might be explained by a reduction in the pool of releasable GH, an alternative explanation is that pretreatment with GRF disrupts the GH release mechanism(s) at a common step(s) beyond cyclic AMP generation and Ca2+ influx.
Co-incubation of cells with somatostatin and GRF (100 nmol/l) partially reversed the desensitizing action of GRF during both 4- and 18-h pretreatments in a dose-dependent manner, with 1 μmol somatostatin/l being most effective. Maximal GRF (100 nmol/l)-stimulated/basal GH release was 4·4 ± 1·0 (mean ± s.e.m., n = four experiments), 1·55 ± 0·09 and 2·43 ± 0·1 for control, GRF-pretreated (4 h) and GRF plus somatostatin-pretreated cells respectively. Comparable values for cells pretreated for 18 h were 3·66 ± 0·44 (n = three experiments), 1·78 ± 0·28 and 3·04 ± 0·04 for control, GRF- and GRF plus somatostatin-pretreated cells. Somatostatin reduced the 50% depletion of cellular GH caused by GRF pretreatment to 15–20%, as well as attenuating GH released during the pretreatment period by 40 ± 5% (mean ± s.e.m., n = seven experiments). Somatostatin restored somatotroph sensitivity of GRF-desensitized cells indicating that, in addition to reversing depletion of the releasable pool of GH, the counter-regulatory hormone also prevents disruption of post-receptor cellular biochemical events which remain to be identified. These results add to the list of GRF actions inhibited by somatostatin and suggest a potentially important role for somatostatin in vivo to maintain somatotroph responsiveness to GRF.
J. Endocr. (1987) 112, 69–76
