Cellular Mechanisms Underlying the Production of Primary Secretory Fluid in Salivary Glands

Martinez, J. Ricardo

doi:10.1177/10454411900010010601

Cited by 37 publications

(19 citation statements)

References 74 publications

(73 reference statements)

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“…This pump-leak fluid secretion model predicts that Cl − influx occurs through a basolateral "pump" and Cl − ions are extruded via an apical "leak" (26). Numerous studies have confirmed that a mechanism similar to this model accounts for fluid secretion by various epithelia, including salivary glands (1,27). The apical Cl − efflux pathway involved in saliva secretion remains unidentified, but there is growing evidence that Tmem16A mediates Cl − efflux in salivary gland secretory cells (6, 7).…”

Section: Discussionmentioning

confidence: 86%

A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland

Catalán

Kondo

Peña-Münzenmayer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Activation of an apical Ca 2+ -activated Cl − channel (CaCC) triggers the secretion of saliva. It was previously demonstrated that CaCCmediated Cl − current and Cl − efflux are absent in the acinar cells of systemic Tmem16A (Tmem16A Cl − channel) null mice, but salivation was not assessed in fully developed glands because Tmem16A null mice die within a few days after birth. To test the role of Tmem16A in adult salivary glands, we generated conditional knockout mice lacking Tmem16A in acinar cells (Tmem16A −/− ). Ca 2+ -dependent salivation was abolished in Tmem16A −/− mice, demonstrating that Tmem16A is obligatory for Ca 2+ -mediated fluid secretion. However, the amount of saliva secreted by Tmem16A −/− mice in response to the β-adrenergic receptor agonist isoproterenol (IPR) was comparable to that seen in controls, indicating that Tmem16A does not significantly contribute to cAMP-induced secretion. Furthermore, IPR-stimulated secretion was unaffected in mice lacking Cftr (Cftr ΔF508/ΔF508 ) or ClC-2 (Clcn2 −/− ) Cl − channels. The time course for activation of IPR-stimulated fluid secretion closely correlated with that of the IPR-induced cell volume increase, suggesting that acinar swelling may activate a volume-sensitive Cl − channel. Indeed, Cl − channel blockers abolished fluid secretion, indicating that Cl − channel activity is critical for IPR-stimulated secretion. These data suggest that β-adrenergic-induced, cAMP-dependent fluid secretion involves a volume-regulated anion channel. In summary, our results using acinar-specific Tmem16A −/− mice identify Tmem16A as the Cl − channel essential for muscarinic, Ca 2+ -dependent fluid secretion in adult mouse salivary glands.acinar cell | secretion | Cl − channel | Tmem16A/Ano1 | Cftr channel

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Section: Discussionmentioning

confidence: 86%

A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland

Catalán

Kondo

Peña-Münzenmayer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The resulting sodium chloride creates an osmotic gradient that drives transepithelial movement of water into the lumen. 11,23,24,26,29 In this study, we report our advances to support salivary acinar-like cell assembly and functional neurotransmitter responses within 2.5D and 3D HA hydrogel systems both in vitro and in vivo.…”

mentioning

confidence: 96%

“…[18][19][20] The transepithelial movement of water via the paracellular pathway is the primary mechanism for fluid secretion by salivary acinar cells. 3,9,[21][22][23][24][25] Fluid secretion can be activated by binding of acetylcholine to M3 muscarinic receptors, and subsequent activation of G proteins. The a-component of the G protein then dissociates and activates phospholipase C, forming inositol triphosphate (IP 3 ) and releasing calcium from intracellular stores.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Implantable Three-Dimensional Salivary Spheroid Assemblies Demonstrate Fluid and Protein Secretory Responses to Neurotransmitters

Pradhan-Bhatt

Harrington

Duncan

et al. 2013

Tissue Engineering Part A

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Radiation treatment in patients with head and neck tumors commonly results in hyposalivation and xerostomia due to the loss of fluid-secreting salivary acinar cells. Patients develop susceptibility to oral infections, dental caries, impaired speech and swallowing, reducing the quality of life. Clinical management is largely unsatisfactory. The development of a tissue-engineered, implantable salivary gland will greatly benefit patients suffering from xerostomia. This report compares the ability of a 2.5-dimensional (2.5D) and a three-dimensional (3D) hyaluronic acid (HA)-based culture system to support functional salivary units capable of producing fluid and phenotypic proteins. Parotid cells seeded on 2.5D, as well as those encapsulated in 3D HA hydrogels, selfassembled into acini-like structures and expressed functional neurotransmitter receptors. Structures in 3D hydrogels merged to form organized 50 mm spheroids that could be maintained in culture for over 100 days and merged to form structures over 500 mm in size. Treatment of acini-like structures with the b-adrenergic agonists norepinephrine or isoproterenol increased granule production and a-amylase staining in treated structures, demonstrating regain of protein secretion. Upon treatment with the M3 muscarinic agonist acetylcholine, acinilike structures activated the fluid production pathway by increasing intracellular calcium levels. The increase in intracellular calcium seen in structures in the 3D hydrogel culture system was more robust and prolonged than that in 2.5D. To compare the long-term survival and retention of acini-like structures in vivo, cell-seeded 2.5D and 3D hydrogels were implanted into an athymic rat model. Cells in 2.5D failed to maintain organized acinilike structures and dispersed in the surrounding tissue. Encapsulated cells in 3D retained their spheroid structure and structural integrity, along with the salivary biomarkers and maintained viability for over 3 weeks in vivo. This report identifies a novel hydrogel culture system capable of creating and maintaining functional 3D salivary spheroid structures for long periods in vitro that regain both fluid and protein secreting functions and are suitable for tissue restoration.

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“…In the case of muscarinic cholinergic stimulation, the signal transduction system involves release of calcium from intracellular stores by inositol triphosphate (IP 3 ) and the subsequent activation of a variety of ion channels and transport systems, ultimately leading to the trans-epithelial movement of water. [4][5][6][7] Since, a healthy flow of saliva is deemed critical for the maintenance of both oral and general health 8 factors that affect the development, function and state of differentiation of salivary gland cells would have an effect on the health and wellbeing of the whole organism.…”

Section: Basic Concepts Of Saliva Secretionmentioning

confidence: 99%

Health benefits of saliva: a review

Dodds

Johnson

Yeh

2005

Journal of Dentistry

554

416

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Cellular Mechanisms Underlying the Production of Primary Secretory Fluid in Salivary Glands

Cited by 37 publications

References 74 publications

A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland

A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland

Implantable Three-Dimensional Salivary Spheroid Assemblies Demonstrate Fluid and Protein Secretory Responses to Neurotransmitters

Health benefits of saliva: a review

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