Abstract
Reduced extracellular Ca2+ is known to promote PTH secretion, while severe Mg2+ depletion has the opposite effect. We have correlated the effects of Mg2+ and Ca2+ on parathyroid hormone (PTH) secretion and cAMP accumulation by rat parathyroid tissues in vitro with the effects of these two metals on adenylate cyclase activity in broken membrane preparations. PTH secretion was maximal at 0.5 mM Ca2+, falling to low levels as the Ca2+ concentration was increased to 2.5 mM. Deletion of Mg2+ from the medium resulted in a marked decrease in PTH secretion at any given Ca2+ concentration. At a constant Ca2+ concentration of 1 mM, both PTH secretion and cAMP production rose to maximal rates as the Mg2+ concentration was increased from 0 to 2 mM. The adenylate cyclase of rat parathyroid membranes was stimulated by both GTP and guanyl-5'-yl-imidodiphosphate [Gpp(NH)p]. EDTA-treated membranes could not be stimulated by Gpp(NH)p. Repletion with Mg2+ was more effective than repletion with Ca2+ in restoring responsiveness to the guanine nucleotide. When membranes were maximally preactivated by Gpp(NH)p and then assayed in the presence of variable concentrations of metal ions, enzyme activity was directly inhibited by Ca2+ and stimulated by Mg2+. Adenylate cyclase sensitivity to Ca2+ inhibition was dependent upon the Mg2+ concentration; in the presence of 0.6 mM Mg2+ a 50% inhibition was produced by 0.05 mM Ca2+, while in the presence of 8 mM Mg2+ a 10-fold higher Ca2+ concentration was required for a similar inhibitory effect. The results suggest that Ca2+ may decrease PTH secretion at least in part by a direct inhibition of adenylate cyclase. Mg2+ may promote PTH secretion either by enhancing the activation of adenylate cyclase by endogenous guanine nucleotides or by competing with Ca2+ for binding to a distinct regulatory site on the enzyme.
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