Generation of specific Ca(2+) signals from Ca(2+) stores and endocytosis by differential coupling to messengers.
It remains unclear how different intracellular stores could interact and be recruited by Ca(2+)-releasing messengers to generate agonist-specific Ca(2+) signatures. In addition, refilling of acidic stores such as lysosomes and secretory granules occurs through endocytosis, but this has never been investigated with regard to specific Ca(2+) signatures. In pancreatic acinar cells, acetylcholine (ACh), cholecystokinin (CCK), and the messengers cyclic ADP-ribose (cADPR), nicotinic acid adenine dinucleotide phosphate (NAADP), and inositol 1,4,5-trisphosphate (IP(3)) evoke repetitive local Ca(2+) spikes in the apical pole. Our work reveals that local Ca(2+) spikes evoked by different agonists all require interaction of acid Ca(2+) stores and the endoplasmic reticulum (ER), but in different proportions. CCK and ACh recruit Ca(2+) from lysosomes and from zymogen granules through different mechanisms; CCK uses NAADP and cADPR, respectively, and ACh uses Ca(2+) and IP(3), respectively. Here, we provide pharmacological evidence demonstrating that endocytosis is crucial for the generation of repetitive local Ca(2+) spikes evoked by the agonists and by NAADP and IP(3). We find that cADPR-evoked repetitive local Ca(2+) spikes are particularly dependent on the ER. We propose that multiple Ca(2+)-releasing messengers determine specific agonist-elicited Ca(2+) signatures by controlling the balance among different acidic Ca(2+) stores, endocytosis, and the ER.
Menteyne
Alexis
A
Centre National de la Recherche Scientifique, Institut de Neurobiologie Alfred Fessard-FRC2118, Laboratoire de Neurobiologie Cellulaire et Moléculaire-UPR9040, Gif sur Yvette F-91198, France.
Burdakov
Anton
A
Charpentier
Gilles
G
Petersen
Ole H
OH
Cancela
Jose-Manuel
JM
D000109:Acetylcholine / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000502:physiology; D036563:Cyclic ADP-Ribose / Q000502:physiology; D004705:Endocytosis / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology; D009249:NADP / Q000031:analogs & derivatives / Q000502:physiology; D022142:Secretory Vesicles / Q000378:metabolism / Q000502:physiology
D036563:Cyclic ADP-Ribose; D009249:NADP; C024376:NAADP; D015544:Inositol 1,4,5-Trisphosphate; D002766:Cholecystokinin; D000109:Acetylcholine; D002118:Calcium