Role of NAADP and cADPR in the induction and maintenance of agonist-evoked Ca2+ spiking in mouse pancreatic acinar cells.
Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic adenosine diphosphate ribose (cADPR) were first demonstrated to mobilize Ca2+ in sea urchin eggs. In the absence of direct measurements of these messengers, pharmacological studies alone have implicated these molecules as intracellular second messengers for specific cell surface receptor agonists. We now report that in mouse pancreatic acinar cells, cholecystokinin, but not acetylcholine, evokes rapid and transient increases in NAADP levels in a concentration-dependent manner. In contrast, both cholecystokinin and acetylcholine-mediated production of cADPR followed a very different time course. The rapid and transient production of NAADP evoked by cholecystokinin precedes the onset of the Ca2+ signal and is consistent with a role for NAADP in the initiation of the Ca2+ response. Continued agonist-evoked Ca2+ spiking is maintained by prolonged elevations of cADPR levels through sensitization of Ca2+ -induced Ca2+ -release channels. This study represents the first direct comparison of NAADP and cADPR measurements, and the profound differences observed in their time courses provide evidence in support of distinct roles of these Ca2+ -mobilizing messengers in shaping specific Ca2+ signals during agonist stimulation.
Yamasaki
Michiko
M
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
Thomas
Justyn M
JM
Churchill
Grant C
GC
Garnham
Clive
C
Lewis
Alexander M
AM
Cancela
Jose-Manuel
JM
Patel
Sandip
S
Galione
Antony
A
D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002766:Cholecystokinin / Q000378:metabolism / Q000494:pharmacology*; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D005453:Fluorescence; D008297:Male; D051379:Mice; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology; D011869:Radioligand Assay; D013997:Time Factors
D036563:Cyclic ADP-Ribose; D009249:NADP; C024376:NAADP; D002766:Cholecystokinin; D000109:Acetylcholine