Signal transduction, calcium and acute pancreatitis

doi:10.1159/000075581

Pancreatology

Volume 3, Issue 6, 2003, Pages 497-505

https://doi.org/10.1159/000075581 Get rights and content

Abstract

Evidence consistently suggests that the earliest changes of acute pancreatitis are intracellular, the hallmark of which is premature intracellular activation of digestive zymogens, accompanied by disruption of normal signal transduction and secretion. Principal components of physiological signal transduction include secretagogueinduced activation of G-protein-linked receptors, followed by generation of inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose. In response, calcium is released from endoplasmic reticulum terminals within the apical, granular pole of the cell, where calcium signals are usually contained by perigranular mitochondria, in turn responding by increased metabolism. When all three intracellular messengers are administered together, even at threshold concentrations, dramatic potentiation results in sustained, global, cytosolic calcium elevation. Prolonged, global elevation of cytosolic calcium is also induced by hyperstimulation, bile salts, alcohol and fatty acid ethyl esters, and depends on continued calcium entry into the cell. Such abnormal calcium signals induce intracellular activation of digestive enzymes, and of nuclear factor κB, as well as the morphological changes of acute pancreatitis. Depletion of endoplasmic reticulum calcium and mitochondrial membrane potential may contribute to further cell injury. This review outlines current understanding of signal transduction in the pancreas, and its application to the pathophysiology of acute pancreatitis.

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^§: Prof. Robert Sutton, DPhil, FRCS, Department of Surgery, University of Liverpool, 5th Floor UCD Block, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA (UK), Tel. +44 151 7064170, Fax +44 151 7065826

View full text

Signal transduction, calcium and acute pancreatitis

Abstract

Acute pancreatitis: The substantial human and financial costs

Gut

Intracellular activation of digestive zymogens in rat pancreatic acini. Stimulation by high doses of cholecystokinin

J Clin Invest

Subcellular kinetics of early trypsinogen activation in acute rodent pancreatitis

Am J Physiol

Intra-acinar cell activation of trypsinogen during caerulein-induced pancreatitis in rats

Am J Physiol

Is an elevated concentration of acinar cytosolic free ionised calcium the trigger for acute pancreatitis?

Lancet

Pancreatic exocrine secretion in acute experimental pancreatitis

Gastroenterology

Effects of caerulein on the apical cytoskeleton of the pancreatic acinar cell

J Clin Invest

Lysosomal enzymes and pancreatitis

Gastroenterology

Progressive disruption of acinar cell calcium signalling is an early feature of caerulein-induced pancreatitis in mice

Gastroenterology

Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-α. Role in regulating cell death and pancreatitis

J Clin Invest

Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene

Nat Genet

The pathobiochemistry of hereditary pancreatitis: Studies on recombinant human cationic trypsinogen

Pancreatology

SPINK1/PSTI polymorphisms act as disease modifiers in familial and idio-pathic chronic pancreatitis

Gastroenterology

Early prediction of severity in acute pancreatitis by urinary trypsinogen activation peptide: A mul-ticentre study

Lancet

Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis

J Clin Invest

Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation

Am J Physiol

The versatility and universality of calcium signalling

Nat Rev Mol Cell Biol

Intracellular signaling mechanisms activated by cholecystokinin-regulating synthesis and secretion of digestive enzymes in pancreatic acinar cells

Annu Rev Physiol

Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells

Proc Natl Acad Sci USA

Calcium signaling and acute pancreatitis: Specific response to a promiscuous messenger

Proc Natl Acad Sci USA

Calcium-mediated mechanisms in chemically induced cell death

Annu Rev Pharmacol Toxicol

Secretagogue-induced digestive enzyme activation and cell injury in rat pancreatic acini

Am J Physiol

The role of intracellular calcium signaling in premature protease activation and the onset of pancreatitis

Am J Pathol

Polarized calcium and calmodulin signaling in secretory epithelia

Physiol Rev

Two different but converging messenger pathways to intracellular Ca2+ release: The roles of nicotinic acid adenine dinucleotide phosphate, cyclic ADP-ribose and inositol trisphosphate

EMBO J

Two functionally distinct cholecystokinin receptors show different modes of action on Ca2+ mobilisation and phospholipid hydrolysis in isolated rat pancreatic acini. Studies using a new cholecystokinin analog, JMV-180

J Biol Chem

Transformation of local Ca2+ spikes to global Ca2+ transients: The combinatorial roles of multiple Ca2+ releasing messengers

EMBO J

Ca2+ flow via tunnels in polarized cells: Recharging of apical Ca2+ stores by focal Ca2+ entry through basal membrane patch

Cell

Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphate-evoked local cytosolic Ca2+ signals

EMBO J

The endoplasmic reticulum as one continuous Ca2+ pool: Visualization of rapid Ca2+ movements and equilibration

EMBO J

Localization of Ca2+ extrusion sites in pancreatic acinar cells

J Biol Chem

Inositol trisphosphate and cyclic ADP-ribose-mediated release of Ca2+ from single isolated pancreatic zymogen granules

Cell

An examination of the role of intracellular ATP in the activation of store-operated Ca2+ influx and Ca2+-dependent capacitance increases in rat baso-philic leukaemia cells

Pflügers Arch

Calcium uptake via endocy-tosis with rapid release from acidifying endo-somes

Curr Biol

Two different but converging messenger pathways to intracellular Ca²⁺ release: The roles of nicotinic acid adenine dinucleotide phosphate, cyclic ADP-ribose and inositol trisphosphate

Two functionally distinct cholecystokinin receptors show different modes of action on Ca²⁺ mobilisation and phospholipid hydrolysis in isolated rat pancreatic acini. Studies using a new cholecystokinin analog, JMV-180

Transformation of local Ca²⁺ spikes to global Ca²⁺ transients: The combinatorial roles of multiple Ca²⁺ releasing messengers

Ca²⁺ flow via tunnels in polarized cells: Recharging of apical Ca²⁺ stores by focal Ca²⁺ entry through basal membrane patch

Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphate-evoked local cytosolic Ca²⁺ signals

The endoplasmic reticulum as one continuous Ca²⁺ pool: Visualization of rapid Ca²⁺ movements and equilibration

Localization of Ca²⁺ extrusion sites in pancreatic acinar cells

Inositol trisphosphate and cyclic ADP-ribose-mediated release of Ca²⁺ from single isolated pancreatic zymogen granules

An examination of the role of intracellular ATP in the activation of store-operated Ca²⁺ influx and Ca²⁺-dependent capacitance increases in rat baso-philic leukaemia cells