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Physiology of saliva

Physiology of saliva. DENT 5302 Topics in Dental Biochemistry Dr. Joel Rudney. Foundation knowledge. DENT 5315 Oral Histology Dr. Koutlas’ salivary gland lectures Ten Cate’s Oral Histology Chapter on Salivary Glands NSCI 6110 Neuroscience for Dental Students

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Physiology of saliva

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  1. Physiology of saliva DENT 5302 Topics in Dental Biochemistry Dr. Joel Rudney

  2. Foundation knowledge • DENT 5315 Oral Histology • Dr. Koutlas’ salivary gland lectures • Ten Cate’s Oral Histology • Chapter on Salivary Glands • NSCI 6110 Neuroscience for Dental Students • Material on neurotransmitters, signal transduction • PHSL 6051 Physiology for Dental Students • Material on water transport, signal transduction • Future foundation for gastrointestinal and kidney

  3. Innervation of stimulation • Dual autonomic innervation of salivary glands • Parasympathetic - secretion of water and ions • Sympathetic - protein secretion • Both act simultaneously and synergistically • Mediated by G-protein coupled receptors • Parasympathetic - M3 muscarinic receptors • Minor players - neuropeptide; nucleotide receptors • VIP, Substance P, nucleotides, etc. • Sympathetic - 2 adrenergic receptors • Minor players -  adrenergic receptors • Two different signal transduction pathways

  4. Muscarinic messages The Phospholipase C - IP3 pathway sends the message Intracellular (and extracellular) Ca2+ flux is a major effector http://www.liv.ac.uk/~petesmif/teaching/1bds_mb/p4/15.gif

  5. Adrenergic messages (Noradrenaline) The adenylate cyclase - cAMP pathway sends the message Effectors are activated by a phophorylation cascade http://www.liv.ac.uk/~petesmif/teaching/1bds_mb/p4/16.gif

  6. Water/electrolyte secretion • Water secretion is driven by osmotic changes • Mediated by ionic fluxes • From basolateral surfaces to the apex (lumen) • Involves ion pumps and channels • Basolateral • Na+-K+-ATPase • Ca2+ activated K+ channel • Na+-K+-2Cl--cotransporter (NKCCl) • Na+-H+ exchanger • Cl-- HCO3- exchanger, plus Carbonic anhydrase • Lumenal • Ca2+ activated Cl- channel • HCO3- channel (Ca2+ activated?) , plus Carbonic anhydrase

  7. Alternative mechanisms Na+-H+ exchanger Cl-- HCO3- exchanger Carbonic anhydrase Na+-H+ exchanger HCO3- channel Carbonic anhydrase Na+-K+-ATPase Ca2+ activated K+ channel Na+-K+-2Cl--cotransporter Ca2+ activated Cl- channel Adapted from Turner and Sugiya, Oral Dis. 2:3-11, 2002

  8. Newly-discovered components • Channels for extracellular Ca2+ in basolateral membrane • Initiate Ca2+ flux that activates other ion channels • hTrp1, others? • How does water cross the apical membrane? • Aquaporin family of water channels • Found in many organ systems • Salivary aquaporin is Aqp5 • Ca2+ activated, open to let water out • Ionic flux pulls the water out - during stimulation • Low level of activation in resting state??

  9. Validation of the model Gresz et al. Am. J. Phsiol. 287: G151-G161, 2004 http://wwwdir.nidcr.nih.gov/dirweb/common/sps.jpg Apical Aquaporin 5 Basolateral Na+-K+-ATPase

  10. Ductal reabsorption • Saliva entering the lumen is isotonic • Saliva entering the mouth is hypotonic • Reabsorption of Na+ and Cl- by striated duct cells • Similar to distal tubules of kidneys • Ion pumps and channels • Lumenal • Na+-H+ exchanger • Cl-- HCO3- exchanger • HCO3- channel • Na+-K+ exchanger • Na+-Cl--cotransporter • Basolateral • Na+-K+-ATPase • Cl- channel

  11. Striated duct cell Lumen Interstitium Nucleus Na+ H+ Cl- 3 Na+ ATP HCO3- Carbonic anhydrase 2 K+ HCO3- Na+ Cl- K+ Na+ Cl- Basolateral membrane folds Mitochondria

  12. Clinical significance • Many points for drugs to interfere with water secretion • Receptors, signal transduction, ion pumps/channels • May explain why xerostomia is a widespread side effect • The M3 receptor is a key point • Autoantibodies to M3 occur in some Sjogren’s patients • Sjogren’s etiology and pathogenesis is very complex • Agonists can be useful in profound xerostomia treatment • Pilocarpine and Cevimiline • Requires some remaining functional tissue • Anti-cholinergics • Most likely to induce xerostomia as a side effect

  13. Research “in the pipeline” • Can we repair damaged salivary glands? • Gene therapy approach • Use viruses to transfect genes into host cells • Infusion into ducts • Ducts are best preserved in Sjogren’s/radiation • Transfect aquaporin into rat duct cells • Not normally present in duct cells • Transfection increased salivary flow • Short-term effect, and only replaces water • Would need to replace many genes for full repair

  14. Tissue engineering • May have more potential in the long run • Step 1: Create a biocompatible scaffold • Must have a duct-like structure • Step 2: Seed with cells • Engineer cells to function like secretory/duct cells OR • Use stem cells and induce differentiation • Step 3: Implant into a patient • Must induce vascularization and innervation • Must suppress rejection or use compatible cells • Will it make saliva??

  15. Protein secretion • A parallel process to water/ion secretion • Both occur side by side in the same secretory cell • There is complex cross-talk between pathways • Classic exocytosis pathway • Endoplasmic reticulum - translation, glycosylation • Golgi - more extensive glycosylation • Condensing vacuole - packaging, condensation • Immature granule - sorting, major branching point • Secretory granule - protein storage • -adrenergic stimulation • Docking, membrane fusion, exocytosis

  16. Classic exocytosis (Noradrenaline) • Immediate response to NA: • Docking and fusion of preformed granules • Release of contents • Long-term response to NA: • Transcription • Translation • Glycosylation • New granules http://www.liv.ac.uk/~petesmif/teaching/1bds_mb/p4/14.gif

  17. Secretory granules • Complex internal structure • Multiple types of proteins, compacted and folded • Membrane proteins that mediate docking and fusion • V(esicle)-SNARES on granule membranes • T(arget)-SNARES on inner side of cell apical membrane • A Ca2+ -dependent process • Example of cross talk between pathways

  18. The other protein pathways • Constitutive-like pathway • Branches off from immature granules • Proteins carried in vesicles to apex - fuse and open • Always active - no stimulation required • Minor regulated pathway • Branches off from immature granules • Proteins carried in vesicles to apex - fuse and open • Triggered by low levels of M3 cholinergic agonists • Vesicle membranes contain t-SNARES for granules • Both are sources of proteins in basal and resting secretions • Vesicle contents are different from granule contents • Explains different protein composition after stimulation

  19. Cross-talk is essential Cholinergic agonist - very low dose Constitutive-like and Minor Regulated only Cholinergic agonist - low dose Constitutive-like and Minor Regulated with occasional granule docking Adrenergic agonist - standard dose Constitutive-like and Minor Regulated plus Classic Exocytosis Adrenergic agonist - standard dose Cholinergic agonist - low dose Constitutive-like and Minor Regulated plus synergistic Classic Exocytosis Castle, A. M. et al. J Cell Sci 2002;115:2963-2973

  20. Supplemental Reading Turner RJ, Sugiya H (2002). Understanding salivary fluid and protein secretion. Oral Diseases 8:3-11.

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