Transcript Important Features of Postpyloric Peptides

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Pâncreas
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Gastrina
 Produzida por células G – antro, duodeno e pâncreas
 Estimulada por peptídeos, aa (Trp e Phe) e Ca++
Aumento de secreção de HCl
Ação trófica
Aumenta motilidade gástrica
Contração muscular da JGE
Colecistoquinina (CCK)
 Produzida por células I –duodeno
 Estimulada por ácidos graxos, aa e produtos da dd.
Aumento de secreção de enzimas pancreáticas
Contração e esvaziamento da vesícula biliar
Aumento de secreção de enteroquinases
Ação trófica no pâncreas
RhoA-GDP
RhoA-GTP
MLC Phosphatase
(Active)
Rho-Kinase
Phosphatase
phosphatase (?)
MLC
SM: Relaxed
Penis: Erect
MLC Phosphatase~P
(Inactive)
MLC-P
SM: Contracted
Penis: Not Erect
MLC kinase
Calmodulin-Ca2+
[Ca2+]i
Inhibition of Tonic Contraction—A Novel Way to Approach Erectile Dysfunction? - Journal of Andrology,
Vol. 23, No. 5,
The state of myosin light chain (MLC) phosphorylation in cavernosal smooth muscle (SM) is regulated by MLC kinase and MLC
phosphatase.
Secretina
 Produzida por células S – duodeno e jejuno
 Estimulada por baixo pH.
Aumento de secreção de H2O e H2CO3
Potencia CCK
Inibe secreção de HCl
Contração do piloro
VIP (vasoactive intestinal peptide)
 Produzida pelo sistema nervoso entérico
 Estimula secreção de eletrólitos e H2O.
Inibição da secreção de HCl
Potencia ação da ACh nas glândulas salivares
Relaxamento do EEI, estômago e vesícula biliar
VIP (vasoactive intestinal peptide)
 Produzida pelo sistema nervoso entérico
 Estimula secreção de eletrólitos e H2O.
Inibição da secreção de HCl
Potencia ação da ACh nas glândulas salivares
Relaxamento do EEI, estômago e vesícula biliar
The upper fundus region of the stomach (Panel A) contains
acid-secreting oxyntic glands (Panel B), which are composed
of parietal cells (Panel C, P), ECL cells, D cells, and X/Alike cells interspersed between mucous cells (Panel C, M).
The lower antrum (Panel A) contains antral glands (Panel B),
which possess the G and D type endocrine cells (Panel C).
Large yellow arrows indicate the major secretory product of
the various endocrine cell types (e.g., gastrin is secreted from
G cells located in the antral glands). Thin black arrows
identify the target cell(s) of a secreted regulatory peptide or
biogenetic amine (e.g., gastrin stimulates CCK2 receptorexpressing ECL cells). The plus (+) and minus (-) symbols
indicate stimulatory and inhibitory effects, respectively.
Abbreviations: ACh, acetylcholine released from cholinergic
enteric neurons; CaSR, calcium-sensing receptor; CCK2,
cholecystokinin type 2 receptors; D, D cell; ENS, enteric
nervous system; ECL, enterochromaffinlike cell; G, G cell;
GRP, gastrin-releasing peptide released from enteric
peptidergic neurons; GRPR, GRP receptor; H2, histamine
type 2 receptor; M, mucous cell; P, parietal cell; SST,
somatostatin; M3, muscarinic type 3 receptor; SST2, and
SST type 2 receptor
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 6.1
Functional organization of the
gastric mucosa.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Table 7.1
Important Features of Postpyloric Peptides
(Continued )
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Table 7.1
Important Features of Postpyloric Peptides
(Continued )
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Table 7.1
Important Features of Postpyloric Peptides
(Continued )
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Table 7.1
Important Features of Postpyloric Peptides
(Continued )
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Table 7.1
Important Features of Postpyloric Peptides
(Continued )
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Table 7.1
Important Features of Postpyloric Peptides
(Continued )
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Table 7.1
Important Features of Postpyloric Peptides
(Continued )
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Table 7.1
Important Features of Postpyloric Peptides
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Table 7.1
Mean increased pancreatic bicarbonate outputs above basal values in response to intravenous
secretin alone (0.03CU/kg/h), CCK-8 alone at four different doses (0.03, 0.06, 0.125, 0.25μg/kg/h),
and a combination of secretin and CCK-8 in five dogs with pancreatic fistulas
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 7.4
Acid secretion is measured in conscious dogs with Heidenhain pouches
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 7.5
Gastric acid output after infusion of secretin (3.3CU/kg/h) alone or in combination with
indomethacin, an inhibitor of prostaglandin synthesis (2mg/kg bolus + 0.5mg/kg/h) in six dogs
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 7.6
Gastric acid outputs in conscious dogs during infusion of pentagastrin (PG) alone, PG
with secretin, PG with serotonin (5-HT), or PG with 5-HT and secretin.
* = p < 0.05 versus PG alone. ** = p < 0.05 versus PG+secretin or PG+5-HT.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 7.7
Pancreatic bicarbonate output (top) in response to a submaximal dose of secretin (100ng/kg/h-IV) alone
(control) or in combination with graded doses of PYY (12.5, 25, 50, 100, 200, 400pmol/kg/h) given each for 30
minutes in conscious dogs
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 7.22
Plasma PYY levels in response to an oral mixed meal in conscious dogs.
Notice that circulating PYY levels are elevated 15 minutes after feeding the meal. B1, B2 = basal plasma PYY levels.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 7.23
Some of the intracellular signaling pathways activated by fibroblast growth factor (FGF) binding to the FGF
receptor (FGFR).
Fibroblast growth factor-heparan sulfate (FGF-HS) binding to the dimerized FGFR causes autophosphorylation of the receptor and activation of multiple
intracellular signaling pathways including the Ras/mitogen-activated protein kinase (MAPK) pathway (1), phospholipase Cγ (PLCγ)/Ca2+ pathway
(2), and the phosphatidylinositol-3 kinase (PI3K)/Akt pathway (3). DAG, diacylglycerol; ERK, extracellular signal–regulated kinase; FRS, FGF receptor
substrate 2; MKP3, MAP kinase phosphatase 3; N-CAM, neural-cell adhesion molecule; PKC, protein kinase C; SOS, Son of sevenless.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 8.11
Agonist-induced contraction is initiated by phosphorylation of
MLC20 by calcium-CaM-dependent MLCK. Influx of
calcium due to opening of voltage-gated calcium channels and
release of calcium from internal stores results in increased
intracellular calcium levels. Calcium binds to CaM forming a
calcium–CaM complex that activates MLCK, which in turn
phosphorylates MLC20 and initiates contraction. Green
triangle represents phosphorylation
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 17.1
Initial contraction mediated by
MLCK activation
Sustained contraction mediated by MLCP inactivation
To maintain phosphorylation of MLC20, MLCP activity is inhibited via two pathways: RhoA/ROCK and PKC. Agonist binding to receptor activates the heterotrimeric Gq/13 resulting in
subsequent activation of RhoA. Activated RhoA activates Rho kinase and phospholipase D (PLD). PLD hydrolyzes phosphatidylcholine to yield phosphatidic acid that is dephosphorylated
to DAG, which then activates PKC isozymes. Activated RhoA kinase phosphorylates regulatory MYPT1 at Threonine 696 resulting in its dissociation from catalytic subunit and inhibition
of phosphatase activity. Activated PKCα phosphorylates CPI-17 at Threonine 38, which is a potent inhibitor of the catalytic PP1cδ-subunit of MLCP, thus inhibiting phosphatase activity.
Both RhoA/ROCK and PKCα pathways regulate sustained contraction by inhibiting MLCP activity.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 17.2
Cyclic nucleotide mediated relaxation by activation of PKA and PKG
Relaxation of smooth muscle is mediated by diffusible gases NO, CO, and neurotransmitters VIP, PACAP. NO is generated by nitric oxide synthase-dependent
degradation of arginine to NO and citrulline. NO stimulates soluble guanylyl cyclase activity and cGMP formation, while VIP stimulates smooth muscle eNOS to
generate NO and stimulates adenylate cyclase activity to form cAMP. cAMP and cGMP, in turn, activate PKA and PKG, respectively.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 17.3
PKA and PKG mediated relaxation
PKA phosphorylates MLCK and RhoA, while PKG phosphorylates RhoA. Phosphorylated MLCK is inactivated, whereas phosphorylated RhoA results in activation of
MLCP. Inactivation of MLCK concomitant with activation of MLCP results in dephosphorylation of MLC20 leading to relaxation. Green triangle represents
phosphorylation
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 17.4
Sequence of events during ACh-induced contraction of GI smooth muscle.
Initial rapid MLC20 phosphorylation and contraction. Step 1: ACh activation of Gq-coupled receptors results in activation of PLC-β1 and hydrolysis of PIP2 into IP3 and DAG. Step 2: IP3
mediates the release of calcium from intracellular calcium stores resulting in a rise of intracellular calcium. Calcium binds to CaM to activate MLCK and RhoA. DAG induces activation of
calcium-dependent cPKC (PKCα). Step 3: Activated MLCK phosphorylates MLC20, which initiates actomyosin cross-bridge formation leading to initial rapid transient contraction. DAGactivated PKCα results in the phosphorylation of CPI-17, a potent inhibitor of PP1cδ, the catalytic subunit of MLCP. Sustained MLC20 phosphorylation and contraction. Step 4: ACh binding to
Gi13- coupled receptors results in further activation of RhoA. Activated RhoA stimulates Rho kinase and PLD. Step 5: Rho kinase phosphorylates MYPT, the regulatory domain of MLCP, and
inhibits MLCP activity. PLD hydrolyzes phosphatidylcholine into phosphatidic acid, which is dephosphorylated to DAG. Step 6: DAG again leads to sustained activation of PKCα, which
phosphorylates CPI-17 and inhibits MLCP activity. Inhibition of MLCP by RhoA and PKC pathways maintains sustained MLC20 phosphorylation leading to sustained contraction.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 17.5
Model illustrating the neural, paracrine, and hormonal regulation of gastric acid secretion
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 47.5
Current model of the crypt–villus distribution of the major acid/base transport proteins shown to play a role
in duodenal HCO-3 secretion.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 48.2
Major cell types of the exocrine pancreas
Acinar cell electron-dense
zymogen granules in its
apical region (arrowheads).
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 49.1 a
Major cell types of the exocrine pancreas
Duct cell with numerous
mitochondria (arrowheads).
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 49.1 b
Organization of the pancreatic acinus
(A) Groups of acinar cells, identified by electron-dense zymogen granules at their apical pole (arrow), empty their
contents into the lumen, which connects to small ducts lined by cuboidal cells (arrowhead).
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 49.2
Organization of the pancreatic acinus
(B) Diagram demonstrating gland organization. Note that acinar groups sometimes surround the duct and do not
form a terminal gland
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 49.2
Organization of the pancreatic acinus
(B) Wax cast of pancreatic ducts
also demonstrated that most small
ducts are terminal structures, some
such as one near the top of the field,
but some form loops (arrowhead).
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 49.3
Pathways leading to secretion in the pancreatic acinar cell.
Several major secretory pathways emerge from immature secretory granules (ISG): storage granules (SG) through the secretagogue- stimulated regulated pathway
(R) and constitutive-like (CL) and minor-regulated (MR) compartments. A constitutive pathway (C) probably emerges from the TGN. The bulk of secretion takes
place through the regulated pathway
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 49.8
Electron micrograph of apical region of an acinar cell.
This shows a secretory granule closely apposed to the apical plasma membrane (left) and an image of zymogen granule membrane that has been incorporated into
the apical plasma membrane following exocytosis (right) allowing for continuity of the granule content with the acinar lumen.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 49.9
Events leading to regulated exocytosis and compensatory membrane retrieval in acinar cells
Actin-coated secretory granules move through the subapical actin network followed by docking and fusion of granule membrane with the apical plasma
membrane. Dissociation of Rab3D, a small GTP binding protein, may regulate these steps. Following membrane fusion and release of secretory proteins into the
acinar lumen, excess membrane is removed from the cell surface and internalized using a clathrin-requiring process
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 49.10
Changes in acinar cell structures and functions during the initiation of acute pancreatitis
Under physiologic conditions, zymogen granule (ZG) exocytosis is restricted to the apical membrane and blocked at the basolateral membrane. Junctional complexes restrict the
paracellular movement of ions and proteins. In acute pancreatitis, apical exocytosis is inhibited, zymogen granules move away from the apical region of the acinar cell, basolateral
exocytosis is allowed, junctional complexes are disrupted and paracellular permeability increases, and autophagy (AV) becomes prominent. These phenomena are linked to the phenotype
of acute pancreatitis with decreased secretion into the pancreatic duct and the activation of digestive enzymes within the acinar cell
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 49.12
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 50.10
Schematic diagram of stimulussecretion coupling of
pancreatic acinar cell protein
secretion
Scanning electron micrographs showing the ductal system of the rat pancreas
(A) Small proximal ducts (arrows) have a characteristic smooth basolateral surface and branch repeatedly without
changing diameter. Arrowheads indicate junctions of the proximal ducts with the acini (A).
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 51.1 a
Scanning electron micrographs showing the ductal system of the rat pancreas
(B) Larger distal ducts (D) have an uneven basal surface and collect secretions from the small proximal ducts. Scale
bar = 20 μm.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 51.1 b
Original model for electrolyte secretion by pancreatic duct epithelium.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 51.5
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 51.7
Electrolyte transporters
expressed in pancreatic duct
epithelium
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 51.8
Sequential mechanism for the
secretin-evoked generation of high
luminal HCO3- concentrations in
the pancreatic ducts of
species such as the guinea pig.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 51.9
Regulation of duct cell
secretion by hormones and
neurotransmitters
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 51.10
Regulation of duct cell
secretion in pathophysiological
conditions.
Neural, hormonal, and paracrine regulators of pancreatic duct secretion.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 52.1
Neural, hormonal, and paracrine regulators of acinar cell secretion
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 52.2
Effect of CCK on pancreatic enzyme secretion and inhibition with atropine in humans.
CCK-8 infusion evoked a dosedependent increase in trypsin (A)
and lipase (B) output in human
volunteers.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 52.4 a
Effect of CCK on pancreatic enzyme secretion and inhibition with atropine in humans.
CCK-8 infusion evoked a dosedependent increase in trypsin (A)
and lipase (B) output in human
volunteers.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 52.4 b
Sites of action for CCK regulation of pancreatic secretion in rats
(A) Physiologic levels of plasma act via
stimulation of the vagal afferent pathways.
In contrast, supraphysiologic plasma CCK
levels act on intrapancreatic neurons and to
a larger extent on pancreatic acini.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 52.5 a
Sites of action for CCK regulation of pancreatic secretion in rats
(B) Adaptive changes occur after chronic vagotomy
involving recruitment of intraduodenal cholinergic
neurons that activate a gastrin-releasing peptide
neural pathway to stimulate secretion
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 52.5 b
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 58.1
Location of SGLT1 in brush border
membrane and GLUT2 of enterocytes
lining the upper villus of rat small
intestine.
Model for glucose absorption across enterocytes.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 58.2
Amino acid transport systems in the intestinal brush border membrane
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 59.3
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 59.2
Mechanisms for the generation of driving
forces for active transport systems in the
intestinal brush border and basolateral
membranes.
Transport of small peptides across the enterocyte from the lumen into blood
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 59.4
Amino acid transport systems in the intestinal basolateral membrane
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 59.5
Role of the FA-handling proteins CD36 and liver FABP (L-FABP) in enterocyte FA uptake
and processing to chylomicrons
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 60.1
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 60.2
TAG pools in enterocytes
Pre-chylomicron formation.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 60.3
Fluid absorption and secretion in the GI tract.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 65.1
(A) Curran/Macintosh three-compartment model of fluid transport.
Isotonic transport of fluid is achieved from compartment I to III via
hypertonic compartment II across semipermeable membranes A and
B as a result of osmoticand hydrostatic pressures developed
because of active ion transport from compartment I to II. (B)
“ Standing gradient ” model of fluid transport. Na+ is actively
transported into the LIS between cells resulting in transcellular
movement of water into the LIS and isotonic transfer of fluid into the
capillary circulation. (C) Routes of water flux across epithelia —
transcellular across the lipid plasma membrane, paracellular across
tight junctions between cells, transcellular via AQP channel proteins
in the plasma membrane. (D) “Solute recirculation” model of fluid
transport. Na+ is actively transported into the LIS resulting in
hypertonic transfer of fluid across the basement membrane and
paracellular water flux. Na+ is transported back into the LIS via
basolateral transporters resulting in net isotonic fluid absorption. (E)
Water cotransport via the sodium/glucose cotransporter SGLT-1.
Water is transported across the lipid bilayer along with Na+ and
glucose as a result of conformational changes during the normal
transport cycle of SGLT-1. (F) Electro-osmosis. Recirculation of Na+
and active transport of Cl - results in an electrical current across the
epithelium. Water is driven across the tight junction by electroosmotic coupling with Na+. (G) Osmosensor feedback. Na+ and water
are transported across epithelial cells (Na+ > water). Concurrently,
water and sodium are transported across the tight junction (water >
Na+). An osmosensor maintains absorbate isotonicity by altering the
rate of tight junctional fluid transfer. (H) “Countercurrent” multiplier in
small intestinal villi. Blood flow through the villous capillary network
results in exchange of small solutes in the villous interstitium. Active
Na + absorption in the epithelium along with countercurrent exchange
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 65.2
Mechanisms of water transport in
epithelia
Model of colonic crypt fluid absorption.
Book - Physiology of the Gastrointestinal Tract – Fifth Edition – Fig 65.5