We studied the relative potencies of extracellular calcium and magnesium in inhibiting PTH release and dopamine-stimulated cAMP accumulation in dispersed bovine parathyroid cells. At 1.0 mmol/L calcium, PTH release was half-maximally suppressed by 1.8 mmol/L magnesium. At calcium concentrations in the subphysiologic range (less than or equal to 100 mumol), on the other hand, magnesium was markedly less potent as an inhibitor of these parameters. With 1.0 mmol/L EGTA and no added calcium (free calcium less than 10(-8) mol/L), half-maximal inhibition of PTH release accumulation occurred at 10 to 15 mmol/L magnesium. Extracellular calcium also markedly potentiated the inhibitory effects of extracellular magnesium on dopamine-stimulated cyclic adenosine monophosphate (cAMP) accumulation. Low magnesium concentrations (less than 1 mmol/L), on the other hand, had little effect on the sensitivity of parathyroid cells to calcium. These results do not fit a model in which calcium and magnesium independently and additively inhibit PTH release in dispersed bovine parathyroid cells. Instead, they demonstrate that the inhibition of PTH release and agonist-stimulated cAMP accumulation by magnesium are critically dependent on the presence of extracellular calcium but not vice versa. These data suggest that extracellular calcium may play an important role in the mechanism(s) by which extracellular magnesium modulates parathyroid function, perhaps through a magnesium-induced uptake of extracellular calcium.