Modulation of the Ca 2+-sensing function of parathyroid cells in vitro and in hyperparathyroidism

Abstract

When raising the extracellular Ca 2+ concentration stepwise from 0.5 to 3.0 mM, bovine parathyroid cells reacted with initial transient and sustained elevations of the cytoplasmic Ca 2+ concentration (Ca 2+ i), as well as more than 50% inhibition of parathyroid hormone (PTH) release. Human parathyroid adenoma cells and bovine cells cultured for 1 day or exposed to a low concentration of a monoclonal antiparathyroid antibody exhibited right-shifted dependencies of PTH release and Ca 2+ i on extracellular Ca 2+ and reduced Ca 2+ i transients. The protein kinase C activator 12- O-tetradecanoylphorbol-13-acetate (TPA) further right-shifted the dose response relationship for Ca 2+ regulated Ca 2+ i of the adenoma cells, whereas the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) tended to normalize it, without affecting Ca 2+ i of normal bovine cells. In cells from an oxyphil adenoma and a parathyroid carcinoma as well as in bovine cells cultured 4 days or exposed to a high concentration of the antiparathyroid antibody, there were no Ca 2+ i transients, very small increases in steady-state Ca 2+ i and nonsuppressible PTH release. The results suggest that reduced availability of a putative Ca 2+-receptor and increased protein kinase C activity may be important factors in the decreased Ca 2+ sensitivity of abnormal parathyroid cells.