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ABSTRACT
A clonal line of osteoblastic cells from a rat osteogenic sarcoma (UMR 106–06), known to possess parathyroid hormone (PTH)-responsive adenylate cyclase, has been shown to increase its rate of K+ uptake mediated by a Na+/K+ pump after exposure to the hormone. The increase in pump activity was not associated with significant changes in K+ efflux or Na+ influx and would therefore be expected to alter intracellular levels of both Na+ and K+. The maximal (75%) increase in pump activity was noted at a PTH concentration of 100 μg/l and half-maximal stimulation at 1·9 μg/l. The effect appeared to be independent of the adenylate cyclase system, since a synthetic peptide antagonist of PTH activation of adenylate cyclase failed to prevent stimulation of the Na+/K+ pump. Similarly, prostaglandin E2, an alternative agonist of adenylate cyclase in these cells, had no effect on the Na+/K+ pump. This novel action of PTH on monovalent cation transport in osteoblast-like cells should provide a clearer insight into the mechanisms of hormone-induced bone resorption.
J. Endocr. (1986) 111, 61–66
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SUMMARY
Whereas the liver is the major site of accumulation of 125I-labelled porcine calcitonin soon after injection in the rat, both human and salmon calcitonin were rapidly taken up in rat kidney, with relatively insignificant amounts found in the liver.
In-vitro studies of degradation of 125I-labelled calcitonins showed that human calcitonin was readily degraded by most rat tissues but the major activity was found in a kidney microsomal fraction, whereas the liver supernatant was most active towards pig calcitonin. Salmon calcitonin was resistant to breakdown by all tissues and fractions except the kidney microsomal fraction, which rapidly degraded it to trichloroacetic acid-soluble fragments. Liver homogenates from a number of mammalian and non-mammalian species degraded pig calcitonin but had little effect on salmon calcitonin.
The results show that the kidney is the most important organ in the metabolism of human and salmon calcitonin in the rat, while confirming that the liver is mainly responsible for the metabolism of porcine calcitonin.
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SUMMARY
When [125I]calcitonin was injected intravenously into rats the major site of accumulation of radioactivity was the liver, whereas [125I]parathyroid hormone was localized chiefly in the kidney.
The distribution of [125I]bovine serum albumin and of Na [125I] was studied for comparison. Although most of the radioactivity of [125I]calcitonin was found in the soluble fractions of liver and kidney, significant binding to liver microsomes occurred. This fraction also bound an appreciable amount of the radioactivity of [125I]parathyroid hormone. The uptake of [125I]calcitonin by liver could be inhibited by the simultaneous injection of unlabelled calcitonin, but not by that of parathyroid hormone, insulin or adrenocorticotrophic hormone.
These results indicate a role for the liver and kidney in the early clearance of calcitonin and parathyroid hormone respectively. It is likely that the liver is the major site of the metabolism of calcitonin in vivo.
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A human lung cancer cell line (BEN cells) with a calcitonin receptor and calcitonin-responsive adenylate cyclase also possesses an insulin receptor. This has been characterized and found to have properties similar to those of other mammalian cell insulin receptors. A receptor number of 58 000 per cell was calculated from curvilinear Scatchard plots, and dissociation of bound labelled insulin by dilution was facilitated by the addition of unlabelled insulin, consistent with negatively co-operative interactions among binding sites.
Preincubation of cells with either calcitonin or insulin led to loss of hormone binding in washed cells. In the case of calcitonin this was associated with loss of adenylate cyclase response. For each hormone the state of down-regulation was characterized by a decrease in receptor number, and for calcitonin there was also a loss in sensitivity of adenylate cyclase. Down-regulation to calcitonin was more rapid than that to insulin and in each case recovery had occurred by 16 h after removal of the hormone. Induction of down-regulation was specific, in that preincubation with one hormone did not influence the subsequent binding or response of the other. Such data are consistent with independent modulation of peptide receptors in the same cell.
