Calcium signalling and pancreatic cell death: apoptosis or necrosis?
Secretagogues, such as cholecystokinin and acetylcholine, utilise a variety of second messengers (inositol trisphosphate, cADPR and nicotinic acid adenine dinucleotide phosphate) to induce specific oscillatory patterns of calcium (Ca(2+)) signals in pancreatic acinar cells. These are tightly controlled in a spatiotemporal manner, and are coupled to mitochondrial metabolism necessary to fuel secretion. When Ca(2+) homeostasis is disrupted by known precipitants of acute pancreatitis, for example, hyperstimulation or non-oxidative ethanol metabolites, Ca(2+) stores (endoplasmic reticulum and acidic pool) become depleted and sustained cytosolic [Ca(2+)] elevations replace transient signals, leading to severe consequences. Sustained mitochondrial depolarisation, possibly via opening of the mitochondrial permeability transition pore (MPTP), elicits cellular ATP depletion that paralyses energy-dependent Ca(2+) pumps causing cytosolic Ca(2+) overload, while digestive enzymes are activated prematurely within the cell; Ca(2+)-dependent cellular necrosis ensues. However, when stress to the acinar cell is milder, for example, by application of the oxidant menadione, release of Ca(2+) from stores leads to oscillatory global waves, associated with partial mitochondrial depolarisation and transient MPTP opening; apoptotic cell death is promoted via the intrinsic pathway, when associated with generation of reactive oxygen species. Apoptosis, induced by menadione or bile acids, is potentiated by inhibition of an endogenous detoxifying enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), suggesting its importance as a defence mechanism that may influence cell fate.
Criddle
D N
DN
MRC Secretory Research Group, Department of Physiology, University of Liverpool, Liverpool, L69 3BX, UK. criddle@liv.ac.uk
Gerasimenko
J V
JV
Baumgartner
H K
HK
Jaffar
M
M
Voronina
S
S
Sutton
R
R
Petersen
O H
OH
Gerasimenko
O V
OV
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009336:Necrosis / Q000503:physiopathology*; D018384:Oxidative Stress / Q000502:physiology; D010179:Pancreas / Q000378:metabolism* / Q000503:physiopathology; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism* / Q000503:physiopathology
D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D002118:Calcium