Cyclic AMP Recruits a Discrete Intracellular Ca 2+ Store by Unmasking Hypersensitive IP 3 Receptors

Inositol 1,4,5-trisphosphate (IP 3 ) stimulates Ca 2+ release from the endoplasmic reticulum (ER), and the response is potentiated by 3',5'-cyclic AMP (cAMP). We investigated this interaction in HEK293 cells using carbachol and parathyroid hormone (PTH) to stimulate formation of IP 3 and cAMP, respectively. PTH alone had no effect on the cytosolic Ca 2+ concentration, but it potentiated the Ca 2+ signals evoked by carbachol. Surprisingly, however, the intracellular Ca 2+ stores that respond to carbachol alone could be both emptied and refilled without affecting the subsequent response to PTH. We provide evidence that PTH unmasks high-affinity IP 3 receptors within a discrete Ca 2+ store. We conclude that Ca 2+ stores within the ER that dynamically exchange Ca 2+ with the cytosol maintain a functional independence that allows one store to be released by carbachol and another to be released by carbachol with PTH. Compartmentalization of ER Ca 2+ stores adds versatility to IP 3 -evoked Ca 2+ signals.