Parathyroid hormone controls the size of the intracellular Ca(2+) stores available to receptors linked to inositol trisphosphate formation.
In HEK 293 cells stably expressing type 1 parathyroid (PTH) receptors, PTH stimulated release of intracellular Ca(2+) stores in only 27% of cells, whereas 96% of cells responded to carbachol. However, in almost all cells PTH potentiated the response to carbachol by about 3-fold. Responses to carbachol did not desensitize, but only the first challenge in Ca(2+)-free medium caused an increase in [Ca(2+)](i), indicating that the carbachol-sensitive Ca(2+) stores had been emptied. Subsequent addition of PTH also failed to increase [Ca(2+)](i), but when it was followed by carbachol there was a substantial increase in [Ca(2+)](i). A similar potentiation was observed between ATP and PTH but not between carbachol and ATP. Intracellular heparin inhibited responses to carbachol and PTH, and pretreatment with ATP and carbachol abolished responses to PTH, suggesting that the effects of PTH involve inositol trisphosphate (IP(3)) receptors. PTH neither stimulated detectable IP(3) formation nor affected the amount formed in response to ATP or carbachol. PTH stimulated cyclic AMP formation, but this was not the means whereby PTH potentiated Ca(2+) signals. We suggest that PTH may regulate Ca(2+) mobilization by facilitating translocation of Ca(2+) between discrete intracellular stores and that it thereby regulates the size of the Ca(2+) pool available to receptors linked to IP(3) formation.
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Department of Pharmacology, Tennis Court Road, Cambridge, CB2 1QJ, United Kingdom.
Taylor
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D000255:Adenosine Triphosphate / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D010281:Parathyroid Hormone / Q000494:pharmacology / Q000502:physiology*; D018016:Receptors, Parathyroid Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D018679:Cholinergic Agonists; D007295:Inositol Phosphates; D010281:Parathyroid Hormone; D018016:Receptors, Parathyroid Hormone; D000255:Adenosine Triphosphate; D002217:Carbachol; D006493:Heparin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium