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Regulation of pancreatic excretory function by ion channels
2015
Viktoria Venglovecz
Morphology of the pancreas
Composition of pancreatic juice
• 1–2 liters of pancreatic juice per day
• acini secrete isotonic, plasma-like fluid
• pancreatic duct absorbs most of the Cl- and secrete HCO3
+
• Human, 140 mM HCO3+
• Mouse and rat, 50–70mM HCO3+
• The cation composition of the juice is nearly constant
Fluid and electrolyte secretion by acinar cells
Na+/K+ ATPase
• hydrolyzes ATP to exchange 3 Na+ in for 2 K+ out
• generate the transcellular Na+ and K+ gradients
• provides the electrochemical gradient
• determines the membrane potential.
K+ channels
• Ca2+ -activated K+ channel
• BK channels
• IK channels
Na+/K+/2Cl- channels
• NKCC1 is ubiquitous
• activated by cell shrinkage
• restore cell volume
• inhibited by the diuretics furosemide and bumetanide
• mediates 70% of the Cl- uptake
• provide most of the Na+ necessary to fuel the Na+/K+ pump•
Na+/H+ and Cl-/HCO3+
• NHE1 and AE2
• NHE1 and AE2 are ubiquitous
• housekeepers of cytoplasmic pH
• activated by small changes in intracellular pH
• NHE1 is activated by acidic pHi
• AE2 is activated by alkaline pHi
• NHE1 and AE2 are involved in many cellular functions including mediation of acinar cell fluid and electrolytesecretion
TMEM16A
• apical Ca2+ -activated Cl- channel
AQUAPORINS
• AQP family consists of 13 members
• water channels• glyceroporins
• AQPs functions: cell adhesion, proliferation, migration, and cell survival
• Diseases: Sjögren’s syndrome and pancreatitis
• Deletion of AQP5 disrupted the integrity of the tight junction and reduced the paracellular water permeability
Fluid and electrolyte secretion by acinar cells
• Secretion is fueled by the basolateral Na+/K+ ATPase pump
• NKCC1 and NHE1 are the main routes of Na+ influx
• Ca2+ -activated K+ channels set the membrane potential at 50 to 60 mV
• NKCC1 is the major route of Cl- influx
• NHE1 and AE2 set cytoplasmic pH at 7.2
• Transcellular Na+ flux
Fluid and electrolyte secretion by ductal cells
TRANSPORTERS AT THE BASOLATERAL MEMBRANE
Na+/H+ exchanger 1 (NHE1)
• electroneutral 1Na+/1H+ exchangers
• NHE1 • ubiquitous• pHi homeostasis • localized at the basolateral membrane• provide a portion of HCO3
+ influx
• NHE2 and NHE3• localized at the luminal membrane • salvage HCO3
+
•
TRANSPORTERS AT THE BASOLATERAL MEMBRANE
Na+/HCO3+ exchanger (NBC)
• expressed at the BASOLATERAL membrane
• electroGENIC transporter
• 1 Na+-2 HCO3+ stoichiometry
• mediates the bulk of basolateral HCO3
+ entry
• Acid-base homeostasis, • Regulation of cell volume and intracellular pH
NBC1 NBC3
• expressed at the LUMINAL membrane
• electroNEUTRAL transporter
• 1 Na+-1 HCO3+ stoichiometry
• Salvage HCO3+
TRANSPORTERS AT THE BASOLATERAL MEMBRANE
TRANSPORTERS AT THE BASOLATERAL MEMBRANE
TRANSPORTERS AT THE LUMINAL MEMBRANE
CFTR
MECHANISM OF HCO3+ SECRETION
MECHANISM OF HCO3+ SECRETION
RELATIONSHIP BETWEEN ACINAR AND DUCTAL CELLS
fluid and HCO3-
enzymes
activating enzymes
Physiology PathophysiologySTRESS
AUTODIGESTION
INFLAMMATION
CELL DEATH
DIGESTION
Alcohol 45%Bile 45%Others 10%
Development of Acute Pancreatitis
InducingFactor
- Bile acid- Ethanol-Other factors
IntracinarEvents
-Pathological Ca2+ signal-Colocalization of lysosomal enzymes and zymogens
-Intrapancreatic trypsinogen activation
-Autodigestion, Inflammation
ImmunResponse
-Leukocyte activation-Cytocines (IL-6, TNFα, etc.)-ROS
ACUTE PANCREATITIS
NO SPECIFICTHERAPY
The Pancreas
Ductal cells Acinar cells
Insufficient electrolyte and fluid secretion
by ductal cells in CF
Destruction of acinar cells
Primary defect in membrane trafficking
of zymogens Correction of the luminal pH reverses the membrane
trafficking defects and largely restores the membrane dynamics
Pancreatic duct obstruction
Freedman SD, Gastroenterology, 2001
Mislocalization of CFTR in AIP
Decreased pancreatic ductal function Reversal by corticosteroid treatment
Ko SB, Gastroenterology, 2010
c
Model of post-ERCP pancreatitis in rats
pH 6.9
pH 7.3
pH 6.0 Pancreatic damage
Noble MD, Gut, 2008
Lower extracellular pH
enhances secretagogue-induced zymogen activation
Bhoomagoud M , Gastroenterology, 2009
Ductal cells Acinar cells
alterations in pancreatic ductal fluid and bicarbonate secretion can increase
patients’ risk to pancreatitis
restoration of pancreatic ductal bicarbonate and fluid secretion may have therapeutic
benefits
Alcohol
Gallstone (bile acid)
Trypsinogen → Trypsin
?
ETIOLOGICAL FACTORS IN ACUTE PANCREATITIS
Venglovecz V et al. Gut 2008;57:1102-12.Ignath I. et al. Pancreas 2009;38:921-9.Venglovecz V, et al. Gut 2011;60:361-9.
Maleth J et al. Gut 2011;60:136-8.
Hegyi P. et al. Gut 2011;60:544-52.Maléth J. et al.unpiblished
The trypsin vicious cycle
Pallagi et al, Gastroenterology 2011 Dec;141(6):2228-2239
HCO3-
HCO3-
HCO3-
HCO3-
To neutralize the acid content secreted by acinar cells
HCO3-
What are the roles of bicarbonate secretion?
HCO3-
To curtail trypsinogen autoactivation within the pancreatic ductal system
To neutralise the acid chyme entering the duodenum from the stomach
To defend the pancreas by washing out the toxic agents
The main pancreatitis-inducing factors (bile acids and ethanol) are strong inhibitors of pancreatic ductal bicarbonate secretion