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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-01262009-144247 |
| Date | 30 January 2009 |
| Creators | Beckel, Jonathan Maxwell |
| Contributors | Lori Birder, H. Richard Koerber, Edwin Levitan, Naoki Yoshimura, Anthony Kanai |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-01262009-144247/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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