Acute Administration of Intact Parathyroid Hormone but Not Its Amino-Terminal Fragment Stimulates Volume of Pancreatic Secretion

El-Shahawy, Mohamed; Fadda, George Z.; Wisner, James R.; Renner, Ian G.; Omachi, Hidecki; Massry, Shaul G.

doi:10.1159/000186219

Cited by 12 publications

(6 citation statements)

References 14 publications

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“…This obser vation is not surprising since other studies have demonstrat ed that many cells responded to 1-84 PTH but not to 1-34 PTH [19][20][21][22][23]. Furthermore, in other systems, the effect of 1-84 PTH is significantly greater than 1-34 PTH [2,[24][25][26].…”

Section: Discussionmentioning

confidence: 69%

Parathyroid Hormone Increases Cytosolic Calcium of Thymocytes

Stojceva-Taneva

Fadda²,

Massry³

1993

Nephron

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Parathyroid hormone (PTH) has been implicated in the genesis of the abnormalities of the immune system in uremia. This action was attributed to the ability of PTH to augment entry of calcium and hence sustain an elevation of the basal level of cytosolic calcium ([Ca²⁺]_i) in the cells of the immune system. However, direct evidence for such an action of the hormone on these cells is lacking. We examined whether PTH affects [Ca²⁺]_i of rat thymocytes and the potential mechanisms of such an effect. 1-84 PTH (0.5,1.0,2.0 × 10^-7M) increased [Ca²⁺]_i in a dose-dependent manner by 31 ± 2.6,73 ± 3.8, and 128 ± 10.8 nM respectively. 1-34 PTH had no effect. The various doses of PTH antagonist ([Tyr-34] bPTH (7-34)NH₂) blocked the PTH-induced rise in [Ca²⁺]_i by 41-67%. Dibutyryl adenosine 3’,5’-cyclic phosphatase (cAMP), forskolin and phorbol ester 12-0-tetradecanoyl-phorbol 13-acetate (TPA) also produced a significant rise in [Ca²⁺]_i of thymocytes. Verapamil blocked the PTH action by 44% but had no effect on the dibutyryl-cAMP-, forskolin- or TPA-induced rise in [Ca²⁺]_i. Absence of calcium in the media abolished the PTH-induced increase in [Ca²⁺]_i and significantly reduced that of dibutyryl cAMP. Staurosprine completely prevented the TPA-induced rise in [Ca²⁺]_i but had no effect on that produced by PTH. 1-84 PTH in the presence of calcium in the medium produced a significant rise in thymocyte cAMP but had no effect in the absence of calcium in the media. The data indicate that (1) thymocytes are a target for PTH and that the intact hormones increased their [Ca²⁺]_i, most likely, through a receptor-hormone interaction, (2) this action of the hormone appears to be partially mediated by its stimulation of cAMP generation and partially by activation of voltage-gated calcium channels, and (3) the rise in [Ca²⁺]_i is, most likely due to both entry of calcium into the thymocytes and mobilization of calcium stores within the cells.

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Section: Discussionmentioning

confidence: 69%

Parathyroid Hormone Increases Cytosolic Calcium of Thymocytes

Stojceva-Taneva

Fadda²,

Massry³

1993

Nephron

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“…In an extensive series of studies directed at the contribution of PTH to the uremic syndrome, Massry and colleagues described various actions of PTH(1-84) that were not shared by PTH(1-34) (372)(373)(374)(375)(376)(377). For example, Meytes et al (372) observed that bPTH(1-84), but not bPTH(1-34), inhibited erythroid burst colony formation in cultured murine bone marrow, although both preparations were biologically active, as measured by cAMP stimulation in renal tissue.…”

Section: Unique Nonclassical Actions Of Intact Pthmentioning

confidence: 99%

Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl-Terminal Ligands

et al. 2004

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PTH is a major systemic regulator of the concentrations of calcium, phosphate, and active vitamin D metabolites in blood and of cellular activity in bone. Intermittently administered PTH and amino-terminal PTH peptide fragments or analogs also augment bone mass and currently are being introduced into clinical practice as therapies for osteoporosis. The amino-terminal region of PTH is known to be both necessary and sufficient for full activity at PTH/PTHrP receptors (PTH1Rs), which mediate the classical biological actions of the hormone. It is well known that multiple carboxyl-terminal fragments of PTH are present in blood, where they comprise the major form(s) of circulating hormone, but these fragments have long been regarded as inert by-products of PTH metabolism because they neither bind to nor activate PTH1Rs. New in vitro and in vivo evidence, together with older observations extending over the past 20 yr, now points strongly to the existence of novel large carboxyl-terminal PTH fragments in blood and to receptors for these fragments that appear to mediate unique biological actions in bone. This review traces the development of this field in the context of the evolution of our understanding of the "classical" receptor for amino-terminal PTH and the now convincing evidence for these receptors for carboxyl-terminal PTH. The review summarizes current knowledge of the structure, secretion, and metabolism of PTH and its circulating fragments, details available information concerning the pharmacology and actions of carboxyl-terminal PTH receptors, and frames their likely biological and clinical significance. It seems likely that physiological parathyroid regulation of calcium and bone metabolism may involve receptors for circulating carboxy-terminal PTH ligands as well as the action of amino-terminal determinants within the PTH molecule on the classical PTH1R.

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“…PTH( 1-84), but not PTH( 1-34), affected hepatic glucose release (10), basal pancreatic juice secretion volume (11), erythropoiesis (12), random migration of polymorphonuclear leukocytes (13), and elastase release from polymorphonuclear leukocytes (14).…”

mentioning

confidence: 99%

Individual and combined effects of intact PTH, amino-terminal, and a series of truncated carboxyl-terminal PTH fragments on alkaline phosphatase activity in dexamethasone-treated rat osteoblastic osteosarcoma cells, ROS 17/2.8

Nakamoto

Baba²,

Fukase³

et al. 1993

Acta Endocrinologica

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The individual and combined effects of intact PTH, amino-terminal, and a series of truncated carboxyl \x=req-\ terminal PTH fragments on alkaline phosphatase activity were examined in dexamethasone-treated rat osteoblastic osteosarcoma cells ROS 17/2.8. Dexamethasone-induced alkaline phosphatase activity was inhibited not only by hPTH(1\p=n-\84) and amino-terminal PTH fragment hPTH(1\p=n-\34), but also by carboxyl-terminal PTH fragment hPTH(69\p=n-\84) in a dose-related fashion. At 10-7 mol/1, hPTH(1\p=n-\84) completely abolished dexamethasone-induced alkaline phosphatase activity, while hPTH(1\p=n-\34) and hPTH(69\p=n-\84) reduced alkaline phosphatase activity to 0.16\m=+-\0.02and 0.80\m=+-\0.03fold, respectively, of the control value obtained in the absence of PTH peptides. The combination of hPTH(1\p=n-\34) and hPTH(69\p=m-\84) resulted in reduction of alkaline phosphatase activity to the level obtained by hPTH(1\x=req-\ 84). The shorter carboxyl-terminal PTH fragment hPTH(71\p=n-\84) did not affect alkaline phosphatase activity or modulate the action of hPTH(1\p=n-\34). The longer carboxyl-terminal PTH fragment hPTH(53\x=req-\ 84) stimulated alkaline phosphatase activity up to 1.23 \ m=+-\ 0.03 fold and partially blunted the inhibitory effect of hPTH(1\p=n-\34) on alkaline phosphatase activity. These findings suggest that carboxyl-terminal PTH fragments could exert diverse effects on the target cells, depending on the length of deletion of amino-terminal amino acids of PTH molecule, and interact with amino-terminal PTH fragment. The two amino-terminal amino acids of hPTH(69\p=n-\84)and the 53\p=n-\68portion of hPTH(53\p=n-\84)might be responsible for the respective inhibitory and stimulatory effects of the peptides on alkaline phosphatase activity.

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Acute Administration of Intact Parathyroid Hormone but Not Its Amino-Terminal Fragment Stimulates Volume of Pancreatic Secretion

Cited by 12 publications

References 14 publications

Parathyroid Hormone Increases Cytosolic Calcium of Thymocytes

Parathyroid Hormone Increases Cytosolic Calcium of Thymocytes

Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl-Terminal Ligands

Individual and combined effects of intact PTH, amino-terminal, and a series of truncated carboxyl-terminal PTH fragments on alkaline phosphatase activity in dexamethasone-treated rat osteoblastic osteosarcoma cells, ROS 17/2.8

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