Fluoride interactions with stimulus-secretion coupling of normal and pathological parathyroid cells

Effects of the GTP binding protein (G-protein) activator NaF on parathyroid hormone (PTH) release, cytoplasmic Ca²⁺ concentration (Ca²⁺]₁) and cAMP content of bovine as well as normal and pathological human parathyroid cells were studied using precautions to avoid CaF₂ precipitation. In 0.5 mm external Ca²⁺, NaF inhibited PTH release and lowered the cAMP content by 50–70% of the effects attained with 3.0 mm Ca²⁺. The NaF-induced increase of Ca²⁺]₁ was considerably smaller than that obtained with rise of external Ca²⁺. It seems likely that NaF activates the inhibitory G_i-protein involved in the regulation of cAMP generation. However, it is unclear whether the sluggish rise of Ca²⁺]₁ induced by NaF is due to a direct effect of a G-protein on Ca²⁺ entry, or somehow related to the G-protein mediated formation of inositol 1,4,5-trisphosphate, which is part of the signal transduction pathway normally initiated by Ca²⁺ binding to its receptor on the parathyroid cell surface. Inhibition of PTH release by NaF probably results from the combined effects on Ca²⁺]₁ and cAMP content. In hyperparathyroidism (HPT) the actions of NaF were not markedly affected despite severe impairments of Ca²⁺-inhibited PTH release and Ca²⁺ triggered increase of Ca²⁺]₁. Consistent with observations of down regulation of the parathyroid Ca²⁺ receptor in HPT, the present results indicate that the disease perturbs signal transduction at a level proximal to the site of action for NaF.