Beckel, Jonathan Maxwell
(2009)
Expression and Function of Urothelial Nicotinic Acetylcholine Receptors.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Classically, the epithelial lining of the urinary bladder, also called the urothelium, has been thought of as a passive barrier against toxins present in urine. However, recent studies are beginning to emerge that demonstrate an active role for the urothelium in the sensory functions of the bladder. For example, the urothelium expresses a number of the same receptors as sensory nerves and can respond to and release transmitters. One such transmitter, acetylcholine, has been shown to be released from the urothelium in response to physical stimuli, and is thought to act back on the urothelium in an autocrine/paracrine manner to effect urothelial signaling. This study was undertaken to determine if the urothelium expresses the proper receptors to respond to acetylcholine, specifically nicotinic acetylcholine receptors, and if these receptors play a role in influencing bladder physiology. Our research indicates that the urothelium expresses the proper nicotinic receptor subunits to form two classes of receptor: 1) α3 heteromeric receptors and 2) α7 homomeric receptors. Both of these classes of urothelial receptor are functional and can alter bladder reflexes in the anesthetized rat. Specifically, α7 receptors mediate an inhibitory pathway as measured by a bladder cystometrogram, while α3 receptors mediate an excitatory pathway. Finally, we examined intracellular and extracellular pathways that may mediate these physiological effects in vivo. These experiments suggest that nicotinic receptors in the urothelium mediate their effects through intracellular calcium signaling, resulting in the modulation of the release of the excitatory transmitter ATP. Specifically, our research indicates that α3 stimulation can potentiate the release of ATP from urothelial cells, while α7 stimulation inhibits it. This effect may be due to the fact that each receptor subtype modulates [Ca+2]i through distinct pathways: α3 receptors through influx of extracellular Ca+2 and α7 receptors through release from intracellular stores. Additionally, our research indicates that α7 receptors can inhibit signaling through α3 receptors, indicating another possible mechanism for the inhibitory effects α7 receptors exhibit in vivo. This research, which is the first to indicate an interaction between two types of nicotinic receptor, suggests that urothelial nicotinic receptors could play a significant role in bladder physiology and may represent a viable target for treatments into bladder pathology.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
30 January 2009 |
| Date Type: |
Completion |
| Defense Date: |
9 January 2009 |
| Approval Date: |
30 January 2009 |
| Submission Date: |
26 January 2009 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
adenosine triphosphate; epithelium; intracellular calcium; micturition; urinary bladder |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-01262009-144247/, etd-01262009-144247 |
| Date Deposited: |
10 Nov 2011 19:31 |
| Last Modified: |
15 Nov 2016 13:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/6308 |
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