Calcium mobilization by IP3, cADPR, NAADP

Pathway Type: 

Image icon calcium_mobilization_panc_2013.jpg69.75 KB


Figure contributed by David Yule

Intracellular Ca2+ signaling in pancreatic acinar cells is initiated by the binding of Acetylcholine to Muscarinic M3 receptors (M3R) and by Cholecystokinin (CCK) to CCK receptors, predominately the CCK1R in mice and rats. Both receptors are classical seven transmembrane domain receptors coupled to guanine nucleotide-binding proteins (G proteins).  Activation of both receptors leads to stimulation of Gαq and increased activity of phospholipase C-β (PLC) which cleaves the membrane phospholipid phosphatidylinositol,4,5,-bisphosphate (PIP2) into diacylglycerol and  inositol 1,4,5-trisphosphate (InsP3). InsP3 diffuses through the cytoplasm and interacts with InsP3 receptors (InsP3R), largely type-2 and -3 present predominantly on the apical endoplasmic reticulum (ER) resulting in Ca2+ release into the cytoplasm. Ca2+ release from InsP3R acts a co-agonist to increase further InsP3R activity and also acts on Ryanodine receptors (RyR) to induce Ca2+ release. Depletion of Ca2+ within the ER results in Ca2+ influx from the extracellular space. The ER Ca2+ sensor has been identified as stromal interaction molecule-1 (stim-1). Following ER depletion, Ca2+ is released from an EF hand present in a domain of stim-1 within the ER lumen and this results in aggregation of several stim-1 molecules. Aggregation of stim-1 is sufficient to gate plasma membrane Ca2+ channels and leads to Ca2+ influx. Good candidates for the channel pore are the proteins Orai-1 and TRPC3. CCK receptor stimulation also stimulates ADP-ribosyl cyclase activity resulting in the formation of two additional Ca2+ mobilizing second messengers; Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic-ADP ribose (cADPr). The particular cyclase responsible has not been defined in pancreas but good candidates include CD38 and CD157. cADPr is generally thought to act on RyR, while the target of NAADP is currently the subject of intense research. Candidates include the RyR and Two Pore Channel (TPC). In addition to the ER, Ca2+ can also be released from a store which accumulates Ca2+ in a manner dependent on a proton gradient- known as the “acidic store”. This pool likely represents the endolysosomal compartment. This pool has been shown to be responsive to InsP3, cADPr and NAADP and may represent the store initially released following receptor stimulation.