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Effects of adenosine and acetylcholine on the lacrimal gland
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Effekter av adenosin och acetylkolin på tårkörteln (Swedish)
Abstract [en]

A balanced tear film is essential for a healthy ocular surface. Insufficient tear production may result in dry eye, a common disorder in the elderly population. Dry eye causes significant discomfort in the patients and may lead to visual impairment and ocular infections. The lacrimal gland secretes water, proteins and electrolytes to the aqueous layer of the tear film. Lacrimal gland secretion is tightly regulated by e.g. neuronally released acetylcholine. The effect of acetylcholine on lacrimal gland secretion was recently found to be potentiated by adenosine. Adenosine is an important signaling molecule acting upon the adenosine receptors: A1, A2A, A2B and A3.

The aim of this thesis was to study effects of adenosine and acetylcholine on intracellular signaling pathways and lacrimal gland secretion. Cholinergic stimulation of secretion was shown to be regulated by the mitogen activated protein kinase p38, a protein previously not known to be involved in exocrine secretion. p38 was activated in response to cholinergic stimulation and inhibition of p38 significantly diminished cholinergic secretion.

When investigating adenosine effects, potentiation of cholinergic secretion was observed by activation of the A2B receptor in addition to the previously studied A1 receptor. An A2 receptor agonist increased cholinergic rabbit lacrimal gland protein secretion at several concentrations. The increase was inhibited by antagonism of the A2B receptor, but not the A2A receptor. When investigating the intracellular signaling pathways following adenosine and acetylcholine receptor activation, adenosine was shown to increase of cAMP levels. An additional increase in cAMP levels was observed after parallel adenosine and cholinergic receptor activation. Inhibition of Ca2+ release from the endoplasmic reticulum had inhibitory effects of cholinergic stimulation of secretion. In addition, the expression of adenosine receptors in a mouse model of autoimmune dry eye was investigated. The results showed a lymphocyte dependent upregulation of A2A receptors in diseased mice compared to controls.

In conclusion, the results in this thesis provide significant contributions in the search of dry eye therapeutics through studies of adenosine and acetylcholine receptor activation.

Place, publisher, year, edition, pages
Växjö, Kalmar: Linnaeus Univeristy Press , 2011. , 76 p.
Series
Linnaeus University Dissertations, 59/2011
Keyword [en]
Lacrimal gland, adenosine, adenosine receptors, signal transduction, exocrine secretion, tear film, dry eye, Sjögren’s syndrome, acetylcholine, mitogen activated protein kinase, p38
National Category
Cell and Molecular Biology Ophthalmology Biochemistry and Molecular Biology Cell Biology Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-13636ISBN: 978-91-86491-97-0 (print)OAI: oai:DiVA.org:lnu-13636DiVA: diva2:432893
Public defence
2011-09-09, Sal N2007, Smålandsgatan 26B, Kalmar, 09:30 (English)
Opponent
Supervisors
Available from: 2011-08-09 Created: 2011-08-01 Last updated: 2011-08-09Bibliographically approved
List of papers
1. p38 mitogen activated protein kinase regulates exocrine secretion in rabbit lacrimal gland.
Open this publication in new window or tab >>p38 mitogen activated protein kinase regulates exocrine secretion in rabbit lacrimal gland.
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:lnu:diva-13660 (URN)
Available from: 2011-08-08 Created: 2011-08-08 Last updated: 2012-01-03Bibliographically approved
2. Adenosine A2 receptor presence, and synergy with cholinergic stimulation in rabbit lacrimal gland
Open this publication in new window or tab >>Adenosine A2 receptor presence, and synergy with cholinergic stimulation in rabbit lacrimal gland
2010 (English)In: Current Eye Research, ISSN 0271-3683, Vol. 35, no 6, 466-474 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Secretion from the lacrimal gland is an important part of the well-being of the eye, and a central part in the search for treatment of dry eye syndrome. Adenosine has stimulatory effects on the lacrimal gland, and can potentiate the effect of the cholinergic agonist carbachol (Cch). The aim of the present study is to investigate the presence of the adenosine A(2) receptor subtypes A(2A) and A(2B) in the rabbit lacrimal gland, and to characterize their role in regulated acinar cell secretion.

METHODS: Expression of the receptors was investigated using reverse transcriptase-PCR (RT-PCR) and immunofluorescence, and secretion effects were studied using a secretion assay in isolated lacrimal gland acinar cells.

RESULTS: Presence of both receptors was detected by RT-PCR and immunofluorescence. The secretion assay revealed a minor effect of stimulation of the A(2) receptors, and a strong synergistic effect with the cholinergic agonist Cch. The synergistic effect was significantly reduced by the A(2B) antagonist PSB 1115, but not by the A(2A) antagonist SCH 58261, indicating that A(2B) is the receptor responsible for this potentiation.

CONCLUSIONS: The study reveals the presence of the adenosine A(2) receptor subtypes as well as a role for them in lacrimal gland secretion, and especially in the synergy with purinergic and cholinergic stimulation.

National Category
Natural Sciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-7814 (URN)20465439 (PubMedID)
Available from: 2010-08-26 Created: 2010-08-26 Last updated: 2014-02-24Bibliographically approved
3. Intracellular events following adenosine and carbachol stimulation of rabbit lacrimal gland secretion
Open this publication in new window or tab >>Intracellular events following adenosine and carbachol stimulation of rabbit lacrimal gland secretion
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:lnu:diva-13661 (URN)
Available from: 2011-08-08 Created: 2011-08-08 Last updated: 2012-01-03Bibliographically approved
4. The adenosine A2a receptor is up-regulated in the lacrimal glands of NOD mice, an experimental model of Sjögren's syndrome
Open this publication in new window or tab >>The adenosine A2a receptor is up-regulated in the lacrimal glands of NOD mice, an experimental model of Sjögren's syndrome
Show others...
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:lnu:diva-13662 (URN)
Available from: 2011-08-08 Created: 2011-08-08 Last updated: 2012-01-03Bibliographically approved

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