Cyclic AMP Recruits a Discrete Intracellular Ca$^{2+}$ Store by Unmasking Hypersensitive IP$_{3}$ Receptors

Abstract

Inositol 1,4,5-trisphosphate (IP3) 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.