Effect of the phorbol ester TPA on PTH secretion Evidence for a role for protein kinase C in the control of PTH release

Abstract

Parathyroid hormone (PTH) secretion is stimulated by low extracellular calcium (Ca²⁺) in association with a reduction in cyosolic Ca²⁺, indicating that this cell type does not conform to classical models of stimulus‐secretion coupling. We used the phorbol ester TPA (12‐O‐tetradecanoyl phorbol 13‐acetate), which directly activates protein kinase C, to investigate the possible role of this enzyme in the unusual secretory properties of the parathyroid cell. TPA causes a dose‐dependent stimulation of PTH release inhibited by high extracellular Ca²⁺ (EC₅₀ = 10 nM) but has relatively little effect on secretion stimulated by low Ca²⁺. This effect was mimicked by the β4‐isomer of phorbol 12,13‐didecanoate which also activates kinase C, but not by the α4‐isomer, which has no effect on this enzyme. TPA does not modify cellular cAMP or cytosolic Ca²⁺ in the parathyroid cell indicating that its effects on PTH secretion are not mediated indirectly via changes in these second messengers. These results suggest that inhibition of PTH release at high Ca²⁺ might be related to a reduction in protein kinase C activity which can be overcome when the enzyme is directly activated by TPA.