Two different but converging messenger pathways to intracellular Ca(2+) release: the roles of nicotinic acid adenine dinucleotide phosphate, cyclic ADP-ribose and inositol trisphosphate.
Hormones and neurotransmitters mobilize Ca(2+) from the endoplasmic reticulum via inositol trisphosphate (IP(3)) receptors, but how a single target cell encodes different extracellular signals to generate specific cytosolic Ca(2+) responses is unknown. In pancreatic acinar cells, acetylcholine evokes local Ca(2+) spiking in the apical granular pole, whereas cholecystokinin elicits a mixture of local and global cytosolic Ca(2+) signals. We show that IP(3), cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) evoke cytosolic Ca(2+) spiking by activating common oscillator units composed of IP(3) and ryanodine receptors. Acetylcholine activation of these common oscillator units is triggered via IP(3) receptors, whereas cholecystokinin responses are triggered via a different but converging pathway with NAADP and cyclic ADP-ribose receptors. Cholecystokinin potentiates the response to acetylcholine, making it global rather than local, an effect mediated specifically by cyclic ADP-ribose receptors. In the apical pole there is a common early activation site for Ca(2+) release, indicating that the three types of Ca(2+) release channels are clustered together and that the appropriate receptors are selected at the earliest step of signal generation.
Cancela
J M
JM
MRC Secretory Control Research Group, The Physiological Laboratory, University of Liverpool, Liverpool L69 3BX, UK.
Gerasimenko
O V
OV
Gerasimenko
J V
JV
Tepikin
A V
AV
Petersen
O H
OH
D000109:Acetylcholine / Q000494:pharmacology; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000502:physiology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002766:Cholecystokinin / Q000494:pharmacology; D036563:Cyclic ADP-Ribose; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007424:Intracellular Fluid / Q000378:metabolism; D017136:Ion Transport; D051379:Mice; D009249:NADP / Q000031:analogs & derivatives* / Q000502:physiology; D010179:Pancreas / Q000166:cytology; D018408:Patch-Clamp Techniques; D011956:Receptors, Cell Surface / Q000502:physiology*; D011949:Receptors, Cholecystokinin / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011956:Receptors, Cell Surface; D011949:Receptors, Cholecystokinin; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; C067025:cyclic ADP-ribose receptor; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D002110:Caffeine; D009249:NADP; C024376:NAADP; D015544:Inositol 1,4,5-Trisphosphate; D002766:Cholecystokinin; D000109:Acetylcholine; D002118:Calcium