PANCREATIC & SALIVARY GLANDS o INTERCALATED DUCT Figure 43-1 Pancreatic acinus and duct morphology.

CT Figure 43-1 Pancreatic acinus and duct morphology. A, The fundamental secretory
CHAPTER 43 - Its proximal end is connected to each acinar lumen unit is composed of an acinus and an intercalated duct. Intercalated ducts merge to
- Fuse with other small ducts that ultimately coalesce to form form intralobular ducts, which in turn merge to form interlobular ducts, and then the
main pancreatic duct. B, The acinar cell is specialized for protein secretion. Large
OVERVIEW OF EXOCRINE GLAND PHYSIOLOGY the INTRALOBULAR DUCT that drains the lobule
condensing vacuoles are gradually reduced in size and form mature zymogen
 I. The pancreas and major salivary glands are compound exocrine - Function: granules that store digestive enzymes in the apical region of the acinar cell. C, The
glands ▪ provide a CONDUIT for the transport of duct cell is a cuboidal cell with abundant mitochondria. Small microvilli project from
 II. Acinar cells are specialized protein-synthesizing cells secretory proteins its apical membrane.
 III. Duct cells are epithelial cells specialized for fluid & electrolyte ▪ its epithelial cell lining plays an important role in
transport MODIFYING THE FLUID AND ELECTROLYTE II. ACINAR CELLS ARE SPECIALIZED PROTEIN-SYNTHESIZING
 IV. Goblet cells contribute to mucin production in exocrine glands COMPOSITION of the primary secretion CELLS

ACINAR CELLS
I. THE PANCREAS AND MAJOR SALIVARY GLANDS ARE o Polarized epithelial cells
COMPOUND EXOCRINE GLANDS o specialized for the production
and export of large quantities of
EXOCRINE GLANDS protein thus equipped with
o specialized secretory organs that contain a branching ductular extensive rough endoplasmic
system through which they release their secretory products reticulum
o EXOCRINE PANCREAS and MAJOR SALIVARY GLANDS are o MOST CX FEATURE: abundance of electron-dense secretory
compound exocrine glands whose principal function is to aid in granules at the apical pole of the cell
digestion - These granules are storage pools of secretory proteins that
- under the control of neural and humoral signals that release their contents after stimulation of the cell by
generate a sequential and coordinated secretory response to neurohumoral agents
an ingested meal
o Salivary glands produce SALIVA PANCREATIC ACINAR CELLS
- lubricates ingested food and initiates the digestion of starch o synthesize proteins and export via the secretory pathway
o PANCREATIC JUICE is rich in: o secretory proteins
▪ HCO3−: neutralizes the acidic gastric contents that enter the - are stored in zymogen granules that are located in the apical
small intestine region of the acinar cell
▪ DIGESTIVE ENZYMES: completes the intraluminal digestion
of ingested carbohydrate, protein, and fat PANCREATIC ACINAR CELLS: SECRETORY PATHWAY
o Contain a rich supply of CELLULAR UPTAKE OF AMINO ACIDS and incorporation into
▪ Nerves: AUTONOMIC nascent proteins in the rough endoplasmic reticulum (ER)
• EFFERENT fibers 
- parasympathetic and sympathetic fibers INCORPORATION into nascent proteins in the rough endoplasmic
- regulate blood flow reticulum (ER)
• AFFERENT FIBERS 
- pain fibers that are activated by glandular o FINAL EXOCRINE GLAND SECRETION: Combined product of Vesicular transport mechanisms then SHUTTLE the newly
inflammation and trauma the acinar cell and the duct cell synthesized proteins to the Golgi complex
▪ blood vessels 
- provides oxygen and nutrients for the gland LOBULES Within the Golgi complex, secretory proteins are SEGREGATED
- carries the hormones that help to regulate secretion (each represents a subdivision of the parenchyma; structural & away from lysosomal enzymes (most requires mannose-6-phosphate
functional secretory units of the gland reside) receptor for sorting to the lysosome)
MORPHOLOGY OF PANCREAS & SALIVARY GLANDS  
(Each lobule drains) Secretory proteins EXIT the Golgi complex in condensing
SECRETORY UNIT INTRALOBULAR DUCT VACUOLES or IMMATURE SECRETORY GRANULES, w/c are
o ACINUS + INTERCALATED DUCT  acidic and maintain the lowest pH within the secretory pathway
o ACINUS (Group of lobules) 
- a cluster of 15 to 100 acinar cells INTERLOBULAR DUCT condensation of the proteins within the vacuole and PINCHING OFF
- synthesize and secrete proteins into the lumen of the  of membrane vesicles
epithelial structure MAIN DUCT 
- PRIMARY SECRETION: final acinar secretion; protein rich (connects the entire gland to the lumen of the gastrointestinal tract) MATURATION of the condensing vacuole to a SECRETORY OR
product ZYMOGEN GRANULE, w/c is about 2/3s of the condensing vacuole
& more electron dense

NMD-1A: TABLE 10 1
 o CYTOSKELETON OF THE ACINAR CELL plays an important role IV. Goblet cells contribute to mucin production in exocrine glands
in the regulation of exocytosis:
▪ Actin network for delivery of the secretory granules to the GOBLET CELLS
apical region of the cell o also present in the exocrine glands
▪ A 2nd actin network: located immediately below the apical o secrete MUCINS, a high MW glycoprotein
membrane, acts as a barrier that blocks fusion of the - when hydrated form MUCUS (fxs: lubrication, hydration &
granules with the apical plasma membrane mechanical protection of surface epithelial cells)
- Reorganizes on stimulation and then releases the - play an important immunological role by binding to
blockade to permit the secretory granules to approach pathogens and interacting with immune-competent cells
the apical plasma membrane
FOUR MAJOR COMPARTMENTS OF THE SECRETORY PATHWAY PANCREATIC ACINAR CELLS
o ROUGH ER III. DUCT CELLS ARE EPITHELIAL CELLS SPECIALIZED FOR FLUID  I. The acinar cell secretes digestive proteins in response to
o GOLGI COMPLEX & ELECTROLYTE TRANSPORT stimulation
o CONDENSING VACUOLES  II. Acetylcholine and cholecystokinin mediate the regulated
o ZYMOGEN GRANULES DUCT EPITHELIAL CELLS secretion of proteins by pancreatic acinar cells
o Contain:  III. Ca2+ is the major second messenger for the secretion of
EXOCYTOSIS BY ACINAR CELLS ▪ ABUNDANT OF proteins by pancreatic acinar cells
o process by which secretory granules release their contents MITOCHONDRIA to  IV. In addition to proteins, the pancreatic acinar cell secretes a
o complex series of events that involves: provide energy for active plasma-like fluid
▪ movement of the granules to the apical membrane transport
▪ fusion of these granules with the membrane ▪ specific MEMBRANE TRANSPORTERS I. THE ACINAR CELL SECRETES DIGESTIVE PROTEINS IN
▪ release of their contents into the acinar lumen ▪ varying degrees of BASOLATERAL MEMBRANE RESPONSE TO STIMULATION
- triggered by neurohormonal stimulation INFOLDINGS that increases the membrane surface area
o During secretion: o synthetic machinery is much less developed than the acinar cells 2 PATHWAYS FOR STIMULATING ACINAR CELLS SECRETION:
- at the onset: surface area of the apical plasma membrane o  transcellular electrolyte movement either by: 1. CONSTITUTIVE SECRETORY PATHWAY
transiently  by 30-fold - activating individual transport proteins - acinar cells are in an UNSTIMULATED state
- steady state: secretory granule membrane is simultaneously - increasing the number of transport proteins in the plasma - secrete low levels of digestive proteins
delivered to and retrieved from the apical membrane membrane. 2. REGULATED PATHWAY
▪ activation of an apical ENDOCYTIC PATHWAY leads o exhibit a considerable degree of morphological heterogeneity - Acinar cells are STIMULATED by neurohumoral proteins
to: retrieval of the secretory granule membrane for along the length of the ductal tree → types of solute transport - cells typically secrete only 10% to 20% of the digestive
recycling;  in the area of the apical plasma proteins within duct cells differ depending on the cell’s location in proteins stored in their granules
membrane back to its resting value the ductal tree - acinar cells secrete 5-10x amylase than constitutive during
30-60 min stimulation period
o exocytosis of the vesicle contents may lead to a TRANSIENT SITE Epithelial CELL CX/S FUNCTION
ACIDIFICATION of the acinar lumen and may modulate adjacent - express very high
epithelial cells: Centroacinar Cells:
At the junction levels of carbonic
small cuboidal;
vacuolar-type H pumps: use the energy of ATP between acinar anhydrase
protruding into the
hydrolysis to TRANSPORT H+ from the cytosol to the and duct cells - presumably play a role
pancreatic lumen
lumen of the vesicle (before exocytosis) in HCO3− secretion
  squamous or low
electrical gradient (inside cuboidal; have an
Chemical gradient for H+ most proximal
positive) across the vesicle abundance of primary function is fluid
(inside acid) (intercalated)
membrane mitochondria; tend to and electrolyte transport
duct
  lack cytoplasmic
Cl− channels in the vesicle membrane can then allow Cl− vesicles
to flow into the vesicle lumen (minute secretion of Cl- more cuboidal
capable of both
contribute to the hydration of proteins within the granule columnar;
Progressing transport of fluid and
before vesicle fusion) contain more
distally electrolytes and
 cytoplasmic vesicles
secretion of proteins
Overall process is HCl movement from cytosol to vesicle and granules
lumen

Water follows by osmosis

NMD-1A: TABLE 10 2
ACINAR CELL EXHIBITS TWO DISTINCT PATTERNS OF REGULATED Note: Simultaneous stimulation of the high-affinity CCK receptor (which B, Applying a physiological
SECRETION: acts via [Ca2+]i) and the VIP receptor (which acts via camp) generates an dose of CCK (i.e., 10 pM)
o MONOPHASIC additive effect on secretion. triggers a series of [Ca2+]i
oscillations. Applying a
- Increasing levels of an agonist that generates a monophasic
supraphysiological conc. of
dose response relationship (e.g., gastrin-releasing peptide DESENSITIZATION CCK (1 nM) (a dose that
[GRP]) causes secretion to reach a maximal level that does o acinar cells that have previously been stimulated may become could initiate pancreatitis)
not fall with higher concentrations of the agent temporarily refractory to subsequent stimulation elicits a single large [Ca2+]i
spike, halts the oscillations,
o BIPHASIC & amylase secretion.
- Increasing levels of a secretagogue that elicits a biphasic High levels of CCK also are
dose response relationship (e.g., cholecystokinin and less effective in causing
amylase secretion
carbachol) causes secretion to reach a maximal level that
subsequently diminishes.
SECRETIN, VIP, AND CCK
- May reflect the presence of functionally separate high-affinity
o increase cAMP production and thus activate protein kinase A
and low-affinity receptors
(PKA) in pancreatic acinar cells
- related to the pathogenesis of acute pancreatitis
o low conc. of CCK → transient stimulation of PKA
NOTE: Amylase
o is released in a fully active form o supraphysiologic conc. of CCK → more prominent & prolong
increase in [cAMP]i and PKA activity
o amylase activity a marker for secretion by acinar cells
o cAMP → increase secretion
o ACh has liitle (if any) on the cAMP signaling pathway
II. ACETYLCHOLINE AND CHOLECYSTOKININ MEDIATE THE
REGULATED SECRETION OF PROTEINS BY PANCREATIC ACINAR
EFFECTORS
CELLS
o Protein targets of activated kinases and phosphatases in the
pancreatic acinar cell are involved in:
M3 & CCK RECEPTORS
- regulating secretion
o Basolateral receptors
- mediate protein synthesis,
o linked to the Gαq heterotrimeric G protein
- growth, transformation, and cell death
o use the phospholipase C (PLC)/Ca2+ signal transduction pathway Figure 43-4 Stimulation of protein secretion from the pancreatic acinar cell. A, the
o lead to increased enzyme secretion from the acinar cell pancreatic acinar cell has at least two pathways for stimulating the insertion of
IV. IN ADDITION TO PROTEINS, THE PANCREATIC ACINAR CELL
zymogen granules and thus releasing digestive enzymes.
SECRETES A PLASMA-LIKE FLUID
M3 MUSCARINIC ACETYLCHOLINE (ACH) RECEPTOR
o acinar cells in the pancreas secrete an ISOTONIC, PLASMA-LIKE
o most important in regulating protein secretion
FLUID
o found in many glandular tissues III. Ca2+ IS THE MAJOR SECOND MESSENGER FOR THE
- NaCl-rich fluid hydrates the dense, protein-rich material that
SECRETION OF PROTEINS BY PANCREATIC ACINAR CELLS
the acinar cells secrete
CHOLECYSTOKININ (CCK) RECEPTORS
- The fundamental transport event is the secretion of Cl−
o CCK1 RECEPTOR Ca2+
across the apical membrane
- Has much higher affinity for CCK than gastrin CCK OR ACH
- Note: Unknown function in human acinar cells EFFECT
STIMULATORY CONC.
o Sustain the basolateral uptake of Cl− into the acinar cell: Na+-K
o CCK2 RECEPTOR Cytosolic free Ca2+ level ([Ca2+]i)
- Equal affinity for CCK & gastrin RESTING STATE pump, Na/K/Cl cotransporter, & K+ channels.
oscillates slowly o secretion of fluid and electrolytes is stimulated by
o Exists in both high affinity & low affinity state -  the frequency of the oscillations, w/c
MAXIMAL SECRETAGOGUES that raise [Ca2+]i.
HIGH AFFINITY CCK LOW AFFINITY CCK is required for CHON synthesis
STIMULATED Low CCK conc. High CCK conc. (PHYSIOLOGIC)
- less effect on the amplitude
o  the membrane conductance of the acinar cell (In the
BY (physiologic) (supraphysiologic) - generates a SUDDEN [Ca2+]i SPIKE Pancreas) - a similar effect is seen on GRP:
EFFECT STIMULATE secretion INHIBIT secretion (2-10x > physiological stimulation) 1) activation of muscarinic receptors by cholinergic neural
NOTE “Muscarinic receptor” May also injure the cells - eliminates / subsequent ABSENCE of pathways
oscillation 2) activation of CCK receptors by humoral pathways
Other receptors found on pancreatic acinar cells: SUPRAMAXIMAL - associated with an INHIBITION OF
o Gastrin releasing peptide (GRP) SECRETION that appears to be mediated o Apical membrane Cl− channels and basolateral membrane K+
o calcitonin gene–related peptide (CGRP) by disruption of the cytoskeletal channels
o insulin components that are required for - effector targets of the activated Ca2+ signaling pathway
o secretin secretion - Phosphorylation of these channels by Ca2+-dependent
o somatostatin kinases increases the open channel probability that
o vasoactive intestinal peptide (VIP) accompanies stimulation.

NMD-1A: TABLE 10 3
 Figure 43-6 HCO3 − secretion
by the cells of the pancreatic
duct. Secretin, via cAMP,
ACINAR CELL TRANSPORT PROCESS phosphorylates and opens
Na-K pump Na/K/Cl cotransporter CFTR Cl− channels. Exit of Cl−
 through apical Cl− channels
generates the Na+ gradient that depolarizes the basolateral
energizes the Na/K/Cl membrane, generating the
electrical gradient favoring
cotransporter electrogenic Na/HCO3
 cotransport. CaM, calmodulin.
Basolateral entry/uptake of Cl+ (K+ exit through K+ Channels)
 2) Cystic Fibrosis Transmembrane Conductance Regulator
PANCREATIC DUCT CELL (CFTR)
Rise in [Cl−]i  I. The pancreatic duct cell secretes isotonic NaHCO3
 - cAMP-activated Cl− channel (Anion channels) that provide
 II. Secretin (via cAMP) and ACh (via Ca2+) stimulate HCO3- HCO3- through Cl- recycling
Drives the secretion of Cl− down its electrochemical gradient secretion by pancreatic ducts
through channels in the apical membrane - also directly serve as conduits for HCO3 – movement from
 III. Apical membrane chloride channels are important sites of the duct cell to the lumen
 neurohumoral regulation
Transepithelial voltage becomes more lumen negative  IV. Pancreatic duct cells may also secrete glycoproteins
 3) Ca2+-activated Cl− channel (rat & mouse)
Na+ moves through the cation-selective paracellular pathway (i.e., - also provides Cl− to the lumen for recycling
I. The pancreatic duct cell secretes isotonic NaHCO3
tight junctions) to join the Cl− secreted into the lumen
 Cl- RECYCLING
PANCREATIC DUCT CELL o facilitated by coactivation of CFTR and SLC26 EXCHANGERS
Water moves through this paracellular pathway & via aquaporin water o principal physiological function: secrete a HCO3−-rich fluid that
channels on the apical and basolateral membranes through direct protein-protein interactions
alkalinizes and hydrates the protein-rich primary secretions of the
 acinar cell.
Net effect: production of an isotonic, NaCl rich fluid (accounts for SOURCE OF INTRACELLULAR HCO3-:
- Accounts for 75% of the total pancreatic secretion 1) direct uptake of HCO3 − via an electrogenic Na/HCO3
~25% of total pancreatic fluid secretion)
 cotransporter (NBCe1-B or SLC4A4)
APICAL HCO3 – SECRETION: - Na+ /HCO3- stoichiometry of 1: 2
Hydrates the dense, protein rich material that the acinar cells secrete 1) Cl-HCO3 exchanger 2) generation of intracellular HCO3 − from CO2 and OH−, catalyzed
- SLC26 family exchanger by CARBONIC ANHYDRASE
- Requires luminal Cl- to secrete intracellular HCO3 − into the
duct lumen

NMD-1A: TABLE 10 4
H+ that accumulates in the cell must be extruded across the basolateral
membrane. (H+ extrusion)
o Na-H exchange
o ATP-dependent H pump
- most active under conditions of neurohumoral stimulation
THREE BASOLATERAL TRANSPORTERS directly or indirectly provide
the intracellular HCO3 – that pancreatic duct cells need for secretion:
1) electrogenic Na/HCO3 cotransporter
2) Na-H exchanger
3) H pump
II. SECRETIN (VIA cAMP) AND ACh (VIA Ca2+) STIMULATE HCO3-
SECRETION BY PANCREATIC DUCTS
For HCO3- secretion, Duct cells have receptors for:
o Stimulator: secretin, ACh, GRP
o Inhibitor: substance P
o CCK: may also modulate ductular secretory processes
SECRETIN
o most important humoral regulator of ductal HCO3− secretion
o from neuroendocrine S cells in response to duodenal pH < 4.5
o activation stimulates:
- adenylyl cyclase → raises cAMP
o can stimulate HCO3- secretion even in low secretin conc. that do
not measurably increase cAMP
o acts by stimulating the apical CFTR Cl− channel and the
basolateral Na/HCO3 cotransporter without affecting the Na-H
exchanger
o SECRETIN RESPONSE MAY BE MEDIATED BY:
1) unmeasurably small increases in total cellular cAMP
2) cAMP increases that are localized to small intracellular
compartments
3) activation of alternative second-messenger pathways
PARASYMPATHETIC DIVISION OF ANS
o also regulate HCO3- secretion
o Postganglionic parasympathetic neurotransmitter ACh →
muscarinic receptors →increases [Ca2+]i & activates Ca2+-
dependent protein kinases (PKC and the calmodulin-dependent
protein kinases)
o ACh effect is inhibited by ATROPINE
GRP
o Also stimulates ductural secretion (rat) but does not increase
[Ca2+]I & does not raise [cAMP]i
o 2nd messenger: unknown
SUBSTANCE P
o Inhibits both basal and stimulated ductular HCO3 – secretion
regardless of whether the secretagogue is secretin, ACh, or GRP
o 2nd messenger: unknown
NMD-1A: TABLE 10
o probably acts at a site that is distal to the generation of second
messengers, such as by inhibiting the Cl-HCO3 exchanger
III. APICAL MEMBRANE CHLORIDE CHANNELS ARE IMPORTANT
SITES OF NEUROHUMORAL REGULATION
EFFECTOR PROTEINS AS TARGETS OF PROTEIN KINASES &
PHOSPHATASES:
1) APICAL Cl- CHANNELS
2) BASOLATERAL K+ CHANNELS
3) Na/HCO3- COTRANSPORTER
CFTR
o low-conductance apical Cl− channel
o has:
▪ nucleotide-binding domains that control channel opening and
closing
▪ regulatory domain with multiple potential PKA and PKC
phosphorylation sites
- neurohumoral agents act on this site
o most important regulators: agents that activate PKA
o PKA activation enhances stimulatory effect of PKA but has little
direct effect on CFTR function
o CFTR Cl− channel is regulated by ATP through two types of
mechanisms:
1) Interaction with the nucleotide-binding domains
2) protein phosphorylation
Ca2+-ACTIVATED Cl− CHANNELS (CaCCS) ON THE APICAL
MEMBRANE (in some species)
o stimulated by:
▪ Ca2+ directly
▪ Stimulating CFTR indirectly
- promotes ATP efflux → Luminal ATP bind to an apical
purinergic receptor → influx of Ca2+ → activation of
CaCCs in an autocrine/ paracrine fashion
IV. PANCREATIC DUCT CELLS MAY ALSO SECRETE
GLYCOPROTEINS
PANCREATIC DUCT CELLS
o PRIMARY FXN: secrete HCO3− and water
o may also synthesize and secrete various high-molecular-weight
proteoglycans
o Unlike the proteins that are secreted by acinar cells, the
glycoproteins synthesized in duct cells are not accumulated in
large secretion granules
- Glycoproteins appear to be continuously synthesized and
secreted from small cytoplasmic vesicles
- Role: protect against protease-mediated injury to mucosal
cells
o SECRETIN increases the secretion of glycoprotein.
- Results from stimulation of glycoprotein synthesis, rather
than from stimulation of vesicular transport or exocytosis
itself
COMPOSITION, FUNCTION, AND CONTROL OF PANCREATIC
SECRETION
 I. Pancreatic juice is a protein-rich, alkaline secretion
 II. In the fasting state, levels of secreted pancreatic enzymes
oscillate at low levels
 III. CCK from duodenal I cells stimulates acinar enzyme secretion,
and secretin from S cells stimulates HCO3- and fluid secretion by
ducts
 IV. A meal triggers cephalic, gastric, and intestinal phases of
pancreatic secretion
 V. The pancreas has large reserves of digestive enzymes for
carbohydrates and proteins, but not for lipids
 VI. Fat in the distal part of the small intestine inhibits pancreatic
secretion
 VII. Several mechanisms protect the pancreas from autodigestion
I. PANCREATIC JUICE IS A PROTEIN-RICH, ALKALINE SECRETION
PANCREAS
o ~1.5 L of pancreatic fluid each day
o has the highest rates of protein synthesis and secretion of any
organ in the body
o delivers between 15 and 100 g of protein into the small intestine
each day
o secretes >20 proteins
o Most of these proteins are either:
- inactive digestive enzyme precursors—zymogens
- active digestive enzymes
o SECRETORY PROTEINS can be classified according to their
substrates:
▪ PROTEASES hydrolyze proteins
▪ AMYLASES digest carbohydrates,
▪ LIPASES and PHOSPHOLIPASEs break down lipids
▪ NUCLEASES digest nucleic acids
OTHER SECRETORY PROTEINS:
GLYCOPROTEIN II (GP2)
o unusual protein with an N-terminal glycosylphosphatidylinositol
moiety that links it to the inner leaflet of the zymogen granule
membrane
o has been implicated in the regulation of endocytosis
o luminal cleavage of the GP2 linkage to the zymogen granule
membrane seems to be necessary for proper trafficking of the
zymogen granule membrane back into the cell from the plasma
membrane
o structurally related to the Tamm-Horsfall protein, which is secreted
by the renal thick ascending limb
5
GPII & LITHOSTATHINE
o may form protein aggregates in the pancreatic juice
o detrimental: pathological formation of protein plugs that can
obstruct the lumen of acini in patients with cystic fibrosis and
chronic pancreatitis

PANCREATITIS-ASSOCIATED PROTEIN
o present in low concentrations in the normal state
o increase up to several hundred-fold during the early phases of
pancreatic injury
o bacteriostatic agent that may help to prevent pancreatic infection
during bouts of pancreatitis

PANCREATIC JUICE IS ALSO RICH IN CA2+ AND HCO3

CALCIUM Figure 43-8 Time course of pancreatic secretion during fasting and feeding. The
o concentrations are: interdigestive output of secretory products (e.g., trypsin) by the pancreas varies
▪ millimolar range inside the organelles of the secretory cyclically and in rough synchrony with the four phases of motor activity (migrating
pathway of the acinar cells motor complexes) of the small intestine, shown by the colored vertical bands.
Feeding causes a massive and sustained increase in trypsin release and switches
- high levels of Ca2+ in the vesicles may be
small-intestinal motility to the fed state.
- required to induce the aggregation of secretory proteins
and to direct them into the secretory pathway
▪ lower in pancreatic secretions after dilution by Ca2+-free
INTESTINAL EFFECT ON
duct secretions PHASES NOTE
MOTILITY SECRETION
Minimal secretion:
BICARBONATE PHASE I QUIESCENT
biliary & gastric
o neutralizes the acidic gastric secretions that enter the duodenum Stimulated by
and allows digestive enzymes to function properly Pancreatic
CCK
o facilitates the micellar solubilization of lipids and mucosal cell PHASE II increases secretion
function increases
Maximal TELENZEPINE,
o stimulated state: flow increases as secretory flow increases II. IN THE FASTING STATE, LEVELS OF SECRETED PANCREATIC Maximal enzyme
interdigestive antagonist of
- exchange of Cl− for HCO3- across the apical membrane of ENZYMES OSCILLATE AT LOW LEVELS secretion the M1
the duct cells → produces a secretory product that is more PHASE secretory rate
Interdigestive muscarinic ACh
alkaline (pH of ~8.1) and has a lower [Cl−] III (migrating motor
CONTROL OF PANCREATIC SECRETION secretory rate: 10- *receptor
- note: Concentrations of Na+ or K+, however, are not complexes reduces
o REGULATED IN fasted & fed state 20%
significantly altered by changes in flow. (MMCs)) interdigestive
PHASE enzyme
BASAL CONDITION DIGESTIVE PERIOD Declining period
o Unstimulated state: flow is low and the electrolyte composition of secretion by
IV
pancreatic juice closely resembles that of blood plasma. Interdigestive (Fasting) Period eating a meal >85%
pancreas secretion: low levels of basal α- adrenergic tone appears to suppress interdigestive
Figure 43-7 Flow pancreatic enzymes pancreatic secretion:  in pancreatic secretion
dependence of pancreatic secretions vary sequential phases to levels that
the electrolyte cyclically and correspond to are 5- to 20-fold higher than PANCREATIC REGULATION
composition of
sequential changes in the motility basal levels o cyclic pattern of interdigestive pancreatic secretion is mediated by
pancreatic fluid. intrinsic and extrinsic mechanisms
Increasing of the small intestine
o predominant mechanism is through PARASYMPATHETIC
secretin levels not
PATHWAYS
only increases the
secretory rate, but o CHOLINERGIC PATHWAYS are the major regulators of
also changes the interdigestive pancreatic secretion
composition of the o basal α- adrenergic tone suppress interdigestive pancreatic
fluid. secretion
o stimulates pancreatic enzyme secretion: CCK, secretin, insulin,
GRP

NMD-1A: TABLE 10 6
III. CCK from duodenal I cells stimulates acinar enzyme secretion, and SECRETIN CEPHALIC PHASE (short lived)
secretin from S cells stimulates HCO3- and fluid secretion by ducts o MOST POTENT HUMORAL STIMULATOR of fluid and HCO3− sight, taste, and smell of food EXOGENOUS CCK
secretion by the pancreas  
CCK o released from neuroendocrine cells (S cells) in the mucosa of the Vagal stimulation – release of Ach enzyme secretion increases
o plays a central role in regulating pancreatic secretion small intestine in response to DUODENAL PH OF <4.5 (blocked by ATROPINE) to 25% to 50%
o released from DUODENAL neuroendocrine cells, I cells 
o Increase 5- to 10-fold within 10 to 30 minutes in response to a meal PANCREATIC HCO3- SECRETION stimulation of muscarinic receptors
o STIMULATOR OF CCK ( CCK RELEASE): CCK SECRETIN on the acinar cell
▪ LIPID in the duodenal lumen (most potent stimulator) AFTER A MEAL   
▪ Protein digestive products (i.e., peptones, amino acids)  to HIGHER LESS THAN those Modest increase in fluid and
▪ Carbohydrate and acid: have little effect EZOGENOUS LEVELS than those generated by a electrolyte secretion but have
▪ CCK-RELEASING FACTORS generated by a meal meal prominent effects on enzyme
- are peptides released by mucosal cells of the duodenum secretion
or secreted by the pancreas INSULIN & OTHER ISLET CELLS HORMONES 
Luminal CCK-releasing factors are degraded o Blood flow from the pancreatic islets moves to the exocrine Dissipates rapidly When food is
FASTING removed
by digestive enzymes → little releasing pancreas through a portal system → allows high concentrations of
STATE
factor remains to stimulate the I cells islet hormones to interact with pancreatic acinar cells → insulin
digestive enzymes are diverted to the modifies the composition of digestive enzymes within the acinar cell
and increases the relative levels of amylase GASTRIC PHASE
digestion of ingested nutrients entering the
FED STATE o Islet hormones may also have trophic effects on the exocrine o stimulant of gastric phase:
gut lumen, and the CCK releasing factors are
pancreas and stimulate its growth 1) distension of the stomach activates the VAGOVAGAL
spared degradation
o Mass of exocrine pancreas is substantially reduced in individual’s GASTROPHRENIC REFLEX
w/ diabetes - important role for chyme in controlling pancreatic
THREE LINES OF EVIDENCE SHOW THAT CCK IS A PHYSIOLOGICAL
secretion occurs after the gastric contents enter the
MEDIATOR OF PANCREATIC PROTEIN SECRETION:
Regulation of exocrine pancreatic secretion is complex, and understanding small intestine
1) CCK levels increase in the serum in response to a meal
this process has been made difficult by the following: 2) protein digestion products (peptones) stimulate G CELLS in
2) Administration of exogenous CCK at the same levels produced by a
1) tissue levels of an exogenously infused hormone may not match antrum of stomach to release GASTRIN (?)
meal stimulates pancreatic protein secretion to higher levels than
those generated by a meal those generated physiologically;
2) because several neurohumoral factors are released in response to a Presence of specific peptides or AA (peptones)
- (the meal may also stimulate the release of inhibitory factors in
meal, the infusion of a single agent may not accurately reflect its 
addition to CCK)
physiological role; stimulates Gastrin release from G cells of the antrum of
3) a specific CCK inhibitor reduces pancreatic protein secretion by
3) specific neurohumoral inhibitors are often unavailable the stomach (G cells in the proximal part of duodenum to
>50%.
4) pancreatic responses may differ depending on the species. a lesser extent)

CCK stimulate enzyme secretion by either:
IV. A MEAL TRIGGERS CEPHALIC, GASTRIC, AND INTESTINAL gastrin/CCK2 receptor and the CCK1 receptor
o DIRECT: CCK1 receptor (unclear)
PHASES OF PANCREATIC SECRETION 
o INDIRECT: parasympathetic (cholinergic) nervous system
stimulate pancreatic secretion
- plays a major role in mediating the intestinal phase of
pancreatic secretion
- Vagal stimulation can drive pancreatic secretion to nearly
o presence of food in the stomach modulates pancreatic secretion
maximum levels
by:
1) affecting the release of hormones
ATROPINE
2) stimulating neural pathways
o antagonist of muscarinic ACh receptors
3) modifying the pH and availability of nutrients in the proximal
o reduces the secretion of enzymes and HCO3− during the intestinal
part of the small intestine
phase of a meal
o inhibits secretion in response to stimulation by physiological levels
of exogenous CCK

GRP
o Major source of GRP appears to be the vagal nerve terminals
o Also stimulates pancreatic enzyme secretion

NMD-1A: TABLE 10 7
 INTESTINAL PHASE

Chyme entering the proximal region of the small intestine


Stimulates a major pancreatic secretory response:
  
1. GASTRIC ACID
entering the duodenum 2.& 3. LIPIDS and, to a lesser degree,
and to a lesser extent, bile peptones
acids and lipids
 
Duodenal pH of <4.5 stimulate duodenal I cells
  
activate a vagovagal
stimulate duodenal S cells
release CCK enteropancreatic
to release SECRETIN
reflex
  
Stimulates duct cells to
stimulates acinar cells
secrete HCO3− and fluid

Note: acid stimulates fluid
& elec secretion to a release digestive
greater extent than CHON enzymes
secretion

PATTERN OF ENZYME SECRETION MEDIATED BY CCK &

VAGOVAGAL PATHWAYS DEPEND ON THE CONTENT OF THE MEAL.

CONTENT ELICIT RESPONSE

LIQUID MEAL ~60% of maximal
SOLID MEAL prolonged response
RICH IN CALORIES Greatest response

CHEMISTRY OF THE INGESTED NUTRIENTS ALSO AFFECTS

PANCREATIC SECRETION VIA THE CCK AND VAGOVAGAL
PATHWAYS

CHEMISTRY EFFECT ON PANCREATIC SECRETION

CHOs LIITLE EFFECT
LIPIDS POTENT STIMULATOR
*TRIGLYCERIDES DO NOT STIMULATE
*MONOGLYCERIDES STIMULATE
*FATTY ACIDS STIMULATE
C-18 fatty acids NEAR MAXIMUM CHON SECRETION
Some FA STIMULATE HCO3- SECRETION
THE GREATER THE SECRETORY
THE LONGER THE FA
RESPONSE
CHON breakdown products INTERMEDIATE
NONESSENTIAL AA LITTLE EFFECT
SOME ESSENTIAL AA STIMULATE
PHENYLALANINE, VALINE,
MOST POTENT AA STIMULATORS
METHIONINE
Generates the initial pancreatic stimulation
PEPTIDES
during the intestinal phase

NMD-1A: TABLE 10 8
FATTY ACIDS REDUCE GASTRIC ACID SECRETION & DELAY
GASTRIC EMPTYING
o MODULATING THE pH in proximal small intestine
The relative POTENCY of the different nutrients in stimulating secretion is
INVERSELY RELATED to the PANCREATIC RESERVES of digestive
enzymes.
o pancreas needs to release only a small portion of its amylase to
digest the carbohydrate in a meal
o release only slightly greater portions of proteolytic enzymes to
digest the proteins.
o Greater fraction of pancreatic lipase has to be released to efficiently
digest the fat in most meals
2) Secretory granule membrane is impermeable to proteins
- Zymogens and active digestive enzymes are sequestered from
proteins in the cytoplasm and other intracellular compartments
3) Enzyme inhibitors such as PANCREATIC TRYPSIN INHIBITOR, co-
packaged in the secretory granule, block the activity of trypsin
aberrantly activated within the granule
- sufficient pancreatic trypsin inhibitor is present in the secretory
granules to block <5% of the potential trypsin activity
4) The CONDENSATION OF ZYMOGENS, THE LOW PH, AND THE
IONIC CONDITIONS within the secretory pathway may further limit
enzyme activity
SALIVARY ACINAR CELLS
 I. Different salivary acinar cells secrete different proteins
 II. Cholinergic and adrenergic neural pathways are the most
important physiological activators of regulated secretion by salivary
acinar cells
 III. Both cAMP and Ca2+ mediate salivary acinar secretion
I. DIFFERENT SALIVARY ACINAR CELLS SECRETE DIFFERENT
PROTEINS

V. THE PANCREAS HAS LARGE RESERVES OF DIGESTIVE 5) Enzymes that become prematurely active within the acinar cell may
ENZYMES FOR CARBOHYDRATES AND PROTEINS, BUT NOT FOR themselves be degraded by other enzymes or be secreted before
LIPIDS they can cause injury

o GREAREST PANCREATIC RESERVES: those required for CHO &

CHON digestion
o Limited: those required for lipid digestion – particularly TAG
hydrolysis
o maldigestion of dietary fat does not occur until 80% to 90% of the
pancreas has been removed
o pancreatic disease w/ extensive destruction of the gland →
MALDIGESTION OR DIEBETES

VI. FAT IN THE DISTAL PART OF THE SMALL INTESTINE INHIBITS

PANCREATIC SECRETION

PRESENCE OF FAT in the distal SOMATOSTATIN TWO MORPHOLOGICALLY DISTINCT

end of the small intestine (particularly SS-28; from ACINAR CELL POPULATIONS
 intestinal D CELLS) 1) PAROTID GLAND
& - secrete a serous (i.e., watery)
PEPTIDE YY (PYY) GLUCAGON (released from product that contains an abundance of α-amylase
pancreatic islet α cells) 2) SUBLINGUAL GLAND
   - Secrete a mucinous product that is composed primarily of
Acting on Decreasing Returns pancreatic secretion FAILURE OF THE PROTECTIVE MECHANISM →PREMATURE mucin glycoprotein.
inhibitory neural pancreatic to interdigestive state after a ACTIVATION of digestive enzymes within the pancreatic acinar cell→ * SUBMANDIBULAR: both serous-type & mucous type acinar cells
pathways blood flow meal initiate PANCREATITIS
  PROLINE RICH- PROTEINS
Reduces pancreatic secretion THREE MECHANISMS LEAD TO THE MIXING OF DIGESTIVE o Also secreted by salivary acinar cells aside from mucin & α –
(inhibition) PROTEASES AND LYSOSOMAL ENZYMES: amylase
o highly glycosylated
1) lysosomal enzymes may be CO-PACKAGED in the secretory o present in the acinar secretory granules and are released by
VII. SEVERAL MECHANISMS PROTECT THE PANCREAS FROM granule exocytosis
AUTODIGESTION 2) CRINOGRAPHY (secretory granules may selectively fuse with
lysosomes) II. Cholinergic and adrenergic neural pathways are the most important
1) Many digestive proteins are stored in secretory granules as 3) AUTOPHAGY (secretory granules, as well as other organelles, may physiological activators of regulated secretion by salivary acinar cells
INACTIVE PRECURSORS OR ZYMOGENS be engulfed by lysosomes)
- Intestinal INTEROKINASE converts trypsinogen to trypsin SALIVARY GLANDS are mostly controlled by the AUTONOMIC
- TRYPSIN initiates conversion of all other zymogens to their NERVOUS SYSTEM.
active form o Both cholinergic and adrenergic neurotransmitters can stimulate
exocytosis by salivary acinar cells

NMD-1A: TABLE 10 9
 TABLE 43-4 AUTONOMIC CONTROL OF SALIVARY SECRETION SALIVARY DUCT CELLS
AUTONOMIC PATHWAY NEUROTRANSMITTER RECEPTOR SIGNALING PATHWAY CELLULAR RESPONSE
TRANSCELLULAR
Ach MUSCARINIC (M3) CHANNEL STEPS
PARASYMPATHETIC Ca2+ FLUID > Protein secretion PROCESS
SUBSTANCE P TACKYKININ NK1 1. apical epithelial Na+
α – ADRENERGIC Ca2+ FLUID > Protein secretion ENaCs channels for Na+ entry into
SYMPATHETIC NOREPINEPHRINE
β - ADRENERGIC cAMP PROTEIN >> fluid secretion the cell from the lumen
2. extrudes this Na+ →
MAJOR AGONISTS OF SALIVARY ACINAR SECRETION ARE: FLUID & ELECTROLYTE SECRETION REABSORPTION
elevated [Na+]i → feedback
- released from postganglionic parasympathetic and sympathetic o 2nd major function of salivary acinar cells OF Na+
Basolateral inhibition by downregulating
nerve terminals o ~90% of total salivary volume output under stimulatory conditions Na-K pump ENaC activity , presumably
o ACh (cholinergic: M3 Receptor o mechanisms in salivary acinar cells are similar to those in via the ubiquitin-protein ligase
o Norepinephrine (adrenergic): α – ADRENERGIC & β - pancreatic acinar cells Nedd4
ADRENERGIC o Mediated by cholinergic & α-adrenergic Cl-HCO3-
o PRIMARY SECRETION: isotonic 1. Entry of Cl− across the
exchanger &
OTHER RECEPTORS IDENTIFIED IN SALIVARY TISSUE INCLUDE ▪ Basolateral uptake of Cl- through N/K/Cl cotransporter (large apical membrane
CFTR
THOSE FOR: (can be in duct cells instead of acinar cells) contribution) * Recycles Cl− absorbed by
o substance P (NK1 receptors) - In conjunction w/ N-K pumps & basolateral K+ channels the
o VIP ▪ apical Cl− and aquaporin water channels: secretion of Cl- & Cl-HCO3 exchanger
o purinergic agonists (P2X7 receptors) water * facilitate both HCO3 −
o neurotensin, ▪ paracellular routes: Na+ & water REABSORPTION CFTR
secretion and Cl−
o prostaglandin ▪ in some glands & species expresses: OF Cl-
reabsorption through
o epidermal growth factor (EGF) • carbonic anhydrase bidirectional Cl− movement
• parallel basolateral Cl-HCO3 exchangers (AE2) across the apical membrane
III. BOTH CAMP AND Ca2+ MEDIATE SALIVARY ACINAR SECRETION • Na-H exchangers (NHE1 and NHE4) Inwardly
• electrogenic Na/HCO3 cotransporters (NBCe1-B or 2. Exit of Cl− across the
rectifying
PROTEIN SECRETION SLC4A4) basolateral membrane of duct
(ClC-2) Cl−
o associated with increases in both [cAMP]i and [Ca2+]i. cells
channels
SALIVARY DUCT CELL SECRETION OF Apical Cl-HCO3 exchangers and CFTR
NOREPINEPHRINE  I. Salivary duct cells produce a hypotonic fluid that is poor in NaCl HCO3- Basolateral Na/HCO3 cotransporters
  and rich in KHCO3 Na-K PUMP basolateral uptake of K+
α-adrenergic, muscarinic, and substance P β-adrenergic  II. Parasympathetic stimulation decreases Na+ absorption, whereas SECRETION OF
receptors receptor mechanism of K+ exit across the apical
aldosterone increases Na+ absorption by duct cells K+
   membrane is not well established
 III. Salivary duct cells also secrete and take up proteins
Activation of
G protein–dependent activation of PLC
cAMP I. SALIVARY DUCT CELLS PRODUCE A HYPOTONIC FLUID THAT IS
  POOR IN NACL AND RICH IN KHCO3
formation of inositol
α – amylase
1,4,5-trisphosphate Diacylglycerol (DAG) Fluid exits the salivary acinus
secretion
(IP3) 
  Passes through intercalated duct w/ typical intercalated duct cells
releases Ca2+ from 
directly activates PKC
intracellular stores Striated duct (High rates of active transport)
 
stimulates Ca2+- Salivary Gland ducts modify the composition of the isotonic, plasma-
dependent protein like primary secretion of the acinar cells
kinases such as PKC
and calmodulin kinase STRIATED DUCT
 o abundant mitochondria and infoldings of the basolateral membrane
Greater effect on fluid secretion give the basal portion of the duct cells a characteristic striated
appearance

NMD-1A: TABLE 10 10
II. PARASYMPATHETIC STIMULATION DECREASES NA+
ABSORPTION, WHEREAS ALDOSTERONE INCREASES NA+
ABSORPTION BY DUCT CELLS
Regulation of duct cell in salivary glands are not well understood.
PARASYMPATHETIC INPUT VIA ACH
o primarily stimulates secretion in the intact salivary gland (i.e., acini
and ducts)
o decreased NaCl absorption more than increased KHCO3
secretion
ADRENERGIC STIMULATION
o activation of the β-adrenergic receptor increases [cAMP]i and
activates the CFTR Cl− channel
CIRCULATING HORMONES
o ALDOSTERONE
- mineralocorticoid hormone that stimulates the absorption of
NaCl and secretion of K+ by salivary duct cells
- not been well examined in salivary duct cells
- in other Na+-absorbing epithelia (e.g., kidney and colon),
aldosterone stimulates Na+ transport by increasing both
ENaC and Na-K pump activity
III. SALIVARY DUCT CELLS ALSO SECRETE AND TAKE UP PROTEINS
DUCT CELLS HANDLE PROTEINS IN THREE WAYS:
1) synthesized by duct cells are secreted into the lumen
2) secreted into the blood
3) reabsorbed from the lumen to the cell
DEGRANULATION OF INTRALOBULAR DUCT CELLS
o occurs primarily in response to α-adrenergic stimulation
o protein secretion
o by duct cells is regulated primarily by the sympathetic division
REGULATION OF DUCT CELLS
o duct cells synthesize polymeric immunoglobulin A (IgA) receptors
- responsible for the basolateral endocytosis of IgA, and
o duct cells synthesize a secretory component
- facilitates the apical release of IgA
o remove organic substances from the duct lumen
o Endocytosis of acinar proteins and other materials (e.g., ferritin) at
the apical pole of the duct cell
o express the transferrin receptor on the apical membrane
- indicates that some regulated endocytosis also occurs in
these cells
- may function to take up specific luminal substances or to
traffic ion transporters to and from the apical plasma
membrane
NMD-1A: TABLE 10
COMPOSITION, FUNCTION, AND CONTROL OF SALIVARY α-AMYLASE
SECRETION o major constituent of saliva and digests a significant amount of the
 I. Depending on protein composition, salivary secretions can be ingested starch
serous, seromucous, or mucous o not essential for effective carbohydrate digestion in the presence
 II. At low flow rates, the saliva is hypotonic and rich in K+, whereas of a normally functioning pancreas (same w/ lingual lipase)
at higher flow rates, its composition approaches that of plasma o partially compensate for the maldigestion in case of pancreatic
 III. Parasympathetic stimulation increases salivary secretion insufficiency
I. DEPENDING ON PROTEIN COMPOSITION, SALIVARY
SECRETIONS CAN BE SEROUS, SEROMUCOUS, OR MUCOUS
SALIVA
o ~90% of saliva is produced by the major salivary glands: the
parotid, the sublingual, and the submandibular glands.
o 10% of saliva comes from numerous minor salivary glands that
are scattered throughout the submucosa of the oral cavity
o Contains PROLINE-RICH PROTEINS
o Also contains smaller amounts of lipase, nucleases, lysozyme,
peroxidases, lactoferrin, secretory IgA, growth factors, regulatory
peptides, and vasoactive proteases such as kallikrein and renin
o PRIMARY FUNCTION:
▪ prevent dehydration of the oral mucosa
▪ provide lubrication for the mastication and swallowing of
ingested food
o senses of taste and, to a lesser extent, smell depend on an
adequate supply of saliva
o maintaining proper oral hygiene by:
- washing away food particles
- killing bacteria (lysozyme and IgA activity)
- contributing to overall dental integrity
II. At low flow rates, the saliva is hypotonic and rich in K+, whereas at
3 TYPES OF SALIVA based on the glycoprotein content of the gland’s
higher flow rates, its composition approaches that of plasma
final secretory product:
o MUCOUS: enriched in mucin
Primary secretion of the salivary acinar cell at rest is plasma-like in
o SEROMUCOUS
composition
o SEROUS: low glycoprotein content; enriched in α-amylase
o Osmolality, reflecting mainly Na+ and Cl−, is ~300 mOsm
o significant difference to plasma: [K+] of the salivary primary
GLAND TYPE OF SALIVA
secretion is always slightly higher than plasma
PAROTID SEROUS o salivary gland stimulation does not significantly alter acinar cell
SUBMANDIBULAR transport function or the composition of the primary secretion
SEROMUCOUS
SUBLINGUAL o leakiness of the tight junctions between acinar cells contributes to
MINOR SALIVARY GLANDS MUCOUS the formation of a plasma-like primary secretory product
PROLINE-RICH PROTEINS NOTE: Human saliva is always hypotonic, and salivary [K+] is always
o Where most abundant proteins in parotid and submandibular greater than plasma [K+].
saliva belong o  salivary flow alkalinizes the saliva and increases its [HCO3−]
o 1/3 of all amino acids are proline → salivary alkalinization
o Exist in acidic, basic, and glycosylated forms o Salivary alkalinization & net HCO3- secretion neutralize the gastric
o have antimicrobial properties acid that normally refluxes into the esophagus
o play an important role in neutralizing dietary TANNINS, which can
damage epithelial cells Composition of the primary salivary secretion is subsequently modified by
o contribute to the lubrication of ingested foods and may enhance the transport processes of the duct cell:
tooth integrity through their interactions with Ca2+ and
hydroxyapatite
11
 Na+ and Cl− are absorbed from the lumen o some ANS fibes: VIP and substance P.
K+ is secreted into the lumen by the duct cells of
most salivary glands Salivary secretion is also regulated, in part, by MINERALOCORTICOIDS
LOW  o ALDOSTERONE produces saliva w/ less Na+ and more K+
(BASAL) GENERATE A K+-RICH, HYPOTONIC SALIVARY o Addison disease
FLOW SECRETION AT REST - adrenal insufficiency
RATES  - opposite effect to aldosterone
inhibits paracellular water movement
 EXOCRINE
SALIVARY GLAND
tightness of the ductal epithelium PANCREAS
HIGHER DISTRIBUTION HOMOGENOUS HETEROGENOUS
final secretory product begins to approach that of the SECRETION PANCREATIC JUICE SALIVA
FLOW
plasma-like primary secretion * 25% isotonic, NaCl
RATES lubricates ingested food
rich fluid
and initiates the
CONTENT * 75% HCO3−-rich
digestion of starch
III. PARASYMPATHETIC STIMULATION INCREASES SALIVARY fluid
SECRETION * Digestive Enzymes
SECRETORY Both secrete an isotonic, plasma-like fluid rich in
SALIVA PRODUCTION EACH DAY: ~1.5 L UNIT proteins
SALIVA RATE OF PRODUCTION - α-amylase, mucins,
~20 different digestive
BASAL CONDITION ~0.5 mL/min ACINAR and proline-rich proteins
zymogens (inactive
DURING SLEEP Slow flow rate CELLS (principal products)
enzyme precursors)
AFTER STIMULATION  10-fold over the basal rate Products - 2 Distinct population:
and enzymes
Parotid & Sublingual
PARASYMPATHETIC CONTROL - contain either:
Some medications (particularly psychiatric drugs)
o most important physiological regulator of salivary secretion in vivo - mixture of zymogens * α-amylase (in the
o Have “anticholinergic” properties that are most commonly
and enzymes parotid gland)
manifested as “dry mouth.”
SECRETORY * mucins (in the
TASTE AND TACTILE STIMULI FROM THE TONGUE
GRANULES sublingual glands)
 Some ANTICHOLINESTERASE AGENTS
- exhibit spherules (focal
Signals Transmitted to The Salivatory Nuclei of The Brainstem o can be found in certain insecticides and nerve gases
- appear uniform nodules of condensation
 o induce excessive salivation
within the granules)
PREGANGLIONIC PARASYMPATHETIC FIBERS TRAVELS IN
- also seen in the large
CN VII CN IX CN V (in some) Found in large distal
distal ducts but in less
    SYMPATHETIC CONTROL ducts
GOBLET abundance
To submandibular Buccal o postganglionic sympathetic fibers from the superior cervical
To otic ganglia Lingual branch CELLS - (in many salivary
ganglia branch ganglia 25% OF EC in distal
glands) mucin is also
    o stimulation increases saliva flow main pancreatic duct
secreted by acinar cells
Postganglionic Lingual & o interruption of sympathetic nerves to the salivary glands has no
parotid Neurohormonal
fibers reach the Postganglionic submandibular major effect on salivary gland function
glands REGULATION (hormones have an Mostly ANS
sublingual and fibers reach the glands o primary stimulator of the myoepithelial cells
important role)
submandibular parotid glands
Glands   MYOEPITHELIAL CELLS
  o losely associated with cells of the acini and proximal (intercalated)
STIMULATE THE SALIVARY GLANDS THROUGH THEIR RELEASE ducts
OF ACH o are stellate cells that have structural features of both epithelial and
smooth-muscle cells
Central impulses triggered by the sight and smell of food also excite the o support the acinar structures
salivatory nuclei and can induce salivation before food is ingested. o decrease the flow resistance of the intercalated ducts during
stimulated secretion
PARASYMPATHETIC STIMULATION o net effect of activation: facilitate secretory flow in the proximal
o necessary for maintaining the normal mass of salivary glands regions of the gland→ minimizing the extravasation of secretory
o Disruption of the parasympathetic fibers to the salivary glands → proteins that could otherwise occur during an acute increase in
GLANDULAR ATROPHY. secretory flow
o modulate blood flow to the gland
NMD-1A: TABLE 10 12
CLINICAL NOTES Mutations in the CF gene (located on chromosome 7) - Mutation to SPINK1 increase the risk of developing
 CYSTIC FIBROSIS  pancreatitis, but alone do not cause disease
 GENETIC CAUSES OF ACUTE & CHRONIC PANCREATITIS Production of a CFTR protein that is abnormally folded
 SJOGREN SYNDROME  ▪ CHYMOTRYPSIN C
Alter the structure & function of CFTR - protease that degrades aberrantly activated trypsin in
CYSTIC FIBROSIS  the pancreatic acinar cell
o most common lethal Autosomal recessive genetic defect ER quality-control system recognizes these molecules as defective - Mutations of chymotrypsin C predispose to pancreatitis
o affects ~1 in 2000  - particularly sensitize those who ABUSE ALCOHOL.
o major cause of morbidity & mortality: PROGRESSIVE Most mutant CFTR molecules are prematurely degraded before they
PULMONARY DISEASE reach the plasma membrane o classic cystic fibrosis generally results in pancreatic insufficiency
- pathophysiology of lung dse in CF is more complex than  at birth and not pancreatitis
that of pancreatic disease Loss of CFTR expression at the plasma membrane - mild mutations in CFTR that result in mild defects in Cl−
- Major finding: airway mucus is thick and viscous as a result  conductance (10% to 20% of normal) – also a risk factor
of insufficient fluid secretion into the airway lumen Disrupts the apical transport processes of the duct cell - mild mutations in CFTR act in concert with alcohol abuse
o reduced activity of CFTR shifts the balance more toward  and SPINK mutations →  disease risk
absorption, and a thick mucous layer is generated that inhibits the Decreased secretion of HCO3 − and water by the duct
ciliary clearance of foreign bodies → increased rate and severity  o Environmental
of infections and thus inflammatory processes that contribute to Protein rich primary (acinar) secretions thicken within the duct lumen o genetics
the destructive process in the lung and lead to ductal obstruction and eventual tissue destruction
o 1ST INDICATION OF ILLNESS: Cough and recurrent respiratory  SJOGREN SYNDROME
infections Ducts appear dilated and obstructed, and fibrotic tissue and fat o chronic and progressive autoimmune disease that affects salivary
o CHILDS SPUTUM: thick and viscous gradually replace the pancreatic parenchyma secretion
o PULMONARY FUNCTION: progressively declines & patients may  o can occur as a:
also experience frequent and severe infections, atelectasis Subsequent deficiency of pancreatic enzymes ▪ primary disease
(collapse of lung parenchyma), bronchiectasis (chronic dilatation  - salivary and lacrimal gland dysfunction only
of the bronchi) recurrent pneumothoraces (air in the intrapleural Maldigestion of nutrients and thus the excretion of fat in the stool ▪ secondary manifestation of a systemic autoimmune disease,
space) (steatorrhea) by patients with CF - rheumatoid arthritis
o causes a characteristic increase in the [NaCl] of sweat, which is o primarily affects women
intermediate in heterozygotes o systemic disease usually does not develop
GENETIC CAUSES OF ACUTE & CHRONIC PANCREATITIS
PULMONARY EPITHELIUM Generation of antibodies that react primarily with the salivary &
o probably both secretes fluid (in a mechanism that requires CFTR) Most of the genetic factors associated with pancreatitis involve digestive lacrimal glands
and absorbs fluid (in a mechanism that requires apical ENaC Na+ enzymes 
channels). o majority lead to an increase in trypsin activity in the acinar cell Lymphocytes infiltrate the glands, and subsequent immunological
injury to the acini leads (One of the targets is the water channel
CFTR HEREDITARY PANCREATITIS AQP5)
o cAMP-activated Cl− channel that is present on the apical plasma o various mutations in cationic trypsinogen are thought to enhance 
membrane of many epithelial cells either the sensitivity of the zymogen (cationic trypsinogen) to Decrease in net secretory function & expression of the Cl-HCO3
o in the pancreas, it is localized to the apical membrane of duct activation or the resistance of the active form (trypsin) to exchanger is lost in the striated duct cells of the salivary gland
cells, where it function to provide the luminal Cl− for Cl-HCO3 degradation. 
exchange o signs & symptoms:
Figure 5-10 Cystic fibrosis PREDISPOSING FACTORS FOR PANCREATITIS: ▪ xerostomia (dry mouth)
transmembrane conductance o factors that determine the levels of active trypsin in the acinar ▪ keratoconjunctivitis sicca (dry eyes)
regulator (CFTR). The CFTR cell: ▪ Loss of salivary function → difficulty tasting, chewing &
Cl− channel has two membrane- ▪ high degree of trypsin activation dry swallowing
spanning domains (MSD1 and
MSD2). A large cytoplasmic
▪ a low level of pancreatic trypsin inhibitor ▪ difficulty with continuous speech
regulatory (R) domain separates ▪ low activity of enzymes that degrade trypsin ▪ complain of a chronic burning sensation in the mouth
the two halves of the molecule, ▪ dry, erythematous oral mucosa with superficial ulceration
each of which has an ATP- o mutations are involved in the last 2 mechanisms. ▪ poor dentition (dental caries, dental fractures, & loss of
binding domain (NBD1 and ▪ SERINE PROTEASE INHIBITOR KAZAL-TYPE 1, OR dentition)
NBD2). The most common SPINK1 ▪ Parotid gland enlargement (commonly present)
mutation in cystic fibrosis is the - A secretory pancreatic trypsin inhibitor
deletion of the phenylalanine at
position 508 (ΔF508) in the - co-packaged with trypsinogen in the secretory pathway
NBD1 domain.
NMD-1A: TABLE 10 13