Saliva physiology

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Saliva physiology

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Physiology of saliva:

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

Foundation knowledge:

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

Innervation of stimulation:

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

Muscarinic messages:

Muscarinic messages http://www.liv.ac.uk/~petesmif/teaching/1bds_mb/p4/15.gif The Phospholipase C - IP 3 pathway sends the message Intracellular (and extracellular) Ca 2+ flux is a major effector

Adrenergic messages:

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

Water/electrolyte secretion :

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 Ca 2+ activated K + channel Na + -K + -2Cl - -cotransporter (NKCCl) Na + -H + exchanger Cl - - HCO 3 - exchanger, plus Carbonic anhydrase Lumenal Ca 2+ activated Cl - channel HCO 3 - channel (Ca 2+ activated?) , plus Carbonic anhydrase

Alternative mechanisms:

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

Newly-discovered components :

Newly-discovered components Channels for extracellular Ca 2+ in basolateral membrane Initiate Ca 2+ 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 Ca 2+ activated, open to let water out Ionic flux pulls the water out - during stimulation Low level of activation in resting state??

Validation of the model:

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

Ductal reabsorption:

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 - - HCO 3 - exchanger HCO 3 - channel Na + -K + exchanger Na + -Cl - -cotransporter Basolateral Na + -K + -ATPase Cl - channel

Striated duct cell:

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

Clinical significance:

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

Research “in the pipeline”:

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

Tissue engineering:

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??

Protein secretion:

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

Classic exocytosis:

Classic exocytosis 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 (Noradrenaline)

Secretory granules:

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 Ca 2+ -dependent process Example of cross talk between pathways

The other protein pathways:

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

Cross-talk is essential:

Cross-talk is essential Castle, A. M. et al. J Cell Sci 2002;115:2963-2973 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

Supplemental Reading:

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

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