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+]i) 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+]i was considerably smaller than that obtained with rise of external Ca2+. It seems likely that NaF activates the inhibitory G1-protein involved in the regulation of cAMP generation. However, it is unclear whether the sluggish rise of [Ca2+]i 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+]i and cAMP content. In hyperparathyroidism (HPT) the actions of NaF were not markedly affected despite severe impairments of Ca(2+)-inhibited PTH release and Ca2+ triggered increase of [Ca2+]i. 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.
Ridefelt
P
P
Department of Surgery, University of Uppsala, Sweden.
Hellman
P
P
Rastad
J
J
Larsson
R
R
Akerström
G
G
Gylfe
E
E
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D006961:Hyperparathyroidism / Q000378:metabolism; D007293:Inosine Triphosphate / Q000378:metabolism; D010279:Parathyroid Diseases / Q000378:metabolism*; D010280:Parathyroid Glands / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism; D012969:Sodium Fluoride / Q000494:pharmacology*
D010281:Parathyroid Hormone; D007293:Inosine Triphosphate; D012969:Sodium Fluoride; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D002118:Calcium