EXOCRINE PANCREAS AND SALIVARY GLANDS

Exocrine Gland-Principal Function: aid in food digestion

Saliva-produced by salivary glands-lubricates ingested food -initiates digestion of starch

Pancreas and Salivary Glands:lobulesintralobular duct:groups of lobulesinterlobular ductsmain duct:Gland main duct lumen (GIT)-lobules: secretory units

Secretory units-composed of acinus intercalated duct

Acinar cells-specialized protein-synthesizing cells-equipped with rER-most characteristic feature: abundance of electron-dense secretory granules at apical pole of cell

-Salivary glandsprincipal CHON products: -amylase, mucins & proline-rich CHONs

Granules-storage pools of secretory CHONS-contain mixture of zymogens & enzymes required for digestion

Secretory granules-Salivary acinar cells -amylase (parotid gland) mucins (sublingual glands)exhibit focal nodules of condensation within granules: Spherules

-pancreasappear uniform

Primary secretion-final acinar secretion-Protein-rich product

Intercalated & Intralobular ducts-provide a conduit for transport of secretory CHONS-Epithelial cells (lining): play a role in modifying fluid and electrolyte composition of primary secretion

Acinar cell + Duct cell final exocrine gland secretion

Duct cells-polarized epithelial cells -transport of electrolytes across apical & basolateral membrane-contain specific membrane transporter & mitochondria to provide energy for active transport-exhibit basolateral membrane infolding that increases membrane surface areas -has high levels of carbonic anhydrase-play a role in HCO3 secretion-Proximal: squamous or low cuboidalhave mitochondria lack cytoplasmic vesiclesfluid and electrolyte transport

-Distal:cuboidal columnarcontain cytoplasmic vesicles and granulestransport of fluid and electrolytesecretion of proteins

Centroacinar cells-small cuboidal epithelial cells -at the junction between acinar and duct cells

Goblet cells-contribute to mucin production in exocrine glands-secrete mucins-hydrated mucinsmucus

Mucins-has immunologic role-bind to pathogens-interact with immune-competent cells-help prevent infections

Pancreatic Acinar Cells-secrete -20 different digestive zymogens and enzymes*zymogen-inactive enzyme precursors-secrete digestive CHONs in response to stimulation-secretes ISOTONIC, plasma like fluid

-NaCl-rich fluid:hydrates the dense, protein rinch material that it secretes

-unstimulated state: secrete LOW levels of digestive CHONsconstitutive secretory pathway

-stimulated:by neurohumoral agentsregulate pathway

-30-60 minute stimulation periodsecrete 5-10 times more amylase than with constitutive release

Patterns of regulated secretion-Monophasic-Biphasic

Monophasic-causes secretion to reach a maximal level that does not fall with higher concentrations of the agent

Biphasic-causes secretion to reach a maximal level that subsequently diminishes with higher concentrations of the agents

Cholecystokinin receptorsMuscarinic Acetylcholine receptors-most important in regulating CHON secretion-linked to Gq heterotrimeric G CHON-use phospholipase C (PLC)/Ca2+ signal transduction pathway-lead to increased enzyme secretion from acinar cell

Cholesytokinin Receptors-distinguished by their structure, affinity for ligands, & tissue distribution-may be activated by CCK or gastrin-able to exist in both a high-affinity and a low-affinity state-physiologic condition: only high-affinity states of CCK/muscarinic receptor are activated-supraphysiologic concentrations: stimulation of lower-affinity states inhibits enzymes secretions and injure acinar cell

CCKA receptor higher affinity for CCK than for gastrin

CCKB receptorequal affinities for CCK and gastrinDesensitization-cells that have been previously stimulated may become temporarily refractory to subsequent stimulation

Ca2+-major second messenger for secretion of CHONS by pancreatic acinar cells

-resting state: [Ca2+]I oscillates slowly

-maximal stimulatory concentrations of CCK/ Ach: frequency of oscillations increaseslittle change in their amplitude

-supramaximal concentrations of CCK/Ach:generate as sudden, large spike in [Ca2+]I oscillations

cGMP-Increase cGMP Nitric oxide metabolism-Inhibition of nitric oxide synthase blocks increase in [cGMP]I after secretagogue stimulation-involved in regulating Ca2+ entry & storage in acinar cell

cAMP-secretin, VIP, CCKincrease cAMP productionactivate protein kinase A (PKA) activity in pancreatic acinar cells

-low concentrations of CCKtransient stimulation of PKA

-Supraphysiologic concentrations of CCKprominent & prolonged increase in [cAMP]i & PKA activity

-Ach has little effect on cAMP signalling pathway

Pancreatic Duct Cell-secrete HCO3 rich fluid that alkalinizes & hydrates protein-rich primary secretions of acinar cells-secrete glycoproteins-secrete an isotonic NaHCO3- solution-have receptors for secretin, ACh, GRP and substance P

-secretin (cAMP) & acetylcholine (Ca2+)stimulate HCO3 secretion by the pancreatic duct

-Apical Membrane Chloride Channelsimportant sites of neurohumoral regulation

secretin, ACh, GRP-stimulate HCO3- secretion

Substance P-inhibits HCO3- secretion

Cl-HC03 exchanger-member of SLC26 family-secretes intracellular HC03- into the duct lumen-luminal Cl- must be available for this exchange process to occur

Cl- recycling -anion channels on the apical membrane of the duct cell provide additional Cl- to the lumen-cystic fibrosis transmembrane conductance regulator (CFTR)cAMP activated Cl- channel present on the apical membrane of pancreatic duct cells

-facilitated by co-activation of CFTR and SLC26 exchangers through direct protein-protein interactions

Intracellular HCO3- Exit Pathways-direct uptake of HCO3- through an electrogenic Na/HC03- cotransporter (NBCel)-generation of intracellular HC03- from CO2 and OH-, catalyzed by carbonic anhydrase

H+ extrusion-Na-H exchange-ATP- dependent H+ pump

Basolateral Transporters -directly/indirectly provide intracellular HCO3- pancreatic duct cells need for secretion1 Electronergic Na/HCO3- cotransporter2 Na-H exchanger3 H+ pump

Secretin and Acetylcholine-stimulate HC03-secretion by pancreatic duct

Secretin-most important humoral regulator of ductal HCO3 secretion