Overactive bladder is a highly prevalent condition, affecting approximately 33 million adults in the United States. Symptoms include frequency, urgency, urge incontinence, or nocturia. As bladder volume increases, involuntary contractions of the detrusor muscle are often associated with overactive bladder. The mechanisms underlying these involuntary contractions have not yet been fully elucidated. Despite the considerable impact this condition has on patients'quality of life, the pharmacological treatment of overactive bladder still remains controversial because of the adverse effects of commonly using anti-muscarinic agents. The purinergic- mediated responses can be another targeting for the treatment of detrusor over activity (DO). P2X receptors mediate contraction and P2Y receptors involve relaxation. P2X receptors are highly expressed in smooth muscle cells but limited expression of P2Y receptors. Thus, we hypothesize that purinergic relaxation might be mediated by activation of P2Y receptors in specialized cells. P2Y receptors are G-protein coupled receptors (GPCR). GPCR modulate the activity of ion channels. The activation of ion channels by P2Y receptors has not been explored in detrusor muscle. We will characterize the functional expression of P2Y receptors, the subsequent increase in intracellular Ca2+ and modulation of Ca2+- activated K+ channels which are involved in detrusor relaxation. Functional expression of small conductance Ca2+-activated K+ (SK) channels in the detrusor muscle has been reported. However the current density of SK channels in detrusor smooth muscle cell was almost negligible at negative membrane potentials. We hypothesize that the expression and activation of SK channels in specialized cells within the detrusor wall are involved in the hyperpolarization and relaxation responses. Recently, our lab reported that specific classes of interstitial cells exist in the bladder. These interstitial cells are identified using antibodies aainst platelet-derived growth factor receptor-? (PDGFR-?+). These cells were distributed throughout detrusor muscle, and were in close apposition with intramural nerve fibers. PDGFR-?+ cells have been described in the gastrointestinal tract and are implicated in purinergic inhibitory neurotransmission. We hypothesize that PDGFR-?+ cells have functional roles on the detrusor purinergic relaxation and abnormality of PDGFR-?+ cells induces DO. In summary, we will characterize a novel population of cells that generate the purinergic inhibitory component of bladder neurotransmission. Isolation of PDGFR-?+ cells and functional study of PDGFR-?+ cells will allow more detailed understanding of purinergic neurotransmission and may reveal new targets for therapies to control detrusor motility. This information will open up important novel areas of investigation in urodynamics physiology and expand new venue of treatment of bladder over activity.

Public Health Relevance

Muscarinic antagonists have been commonly used for the treatment of overactive bladder, however they have serious side effects. Therefore targeting muscarinic receptors in smooth muscle cells for the treatment of detursor overactivity is problematic. In this proposal, we will provide novel areas of investigation in urodynamics physiology and add non-muscarinic venues for the treatment of overactive bladder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK098388-01A1
Application #
8632515
Study Section
Special Emphasis Panel (UGPP)
Program Officer
Mullins, Christopher V
Project Start
2013-09-15
Project End
2018-07-31
Budget Start
2013-09-15
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$312,113
Indirect Cost
$94,613
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Lee, Haeyeong; Koh, Byoung H; Peri, Lauren E et al. (2014) Purinergic inhibitory regulation of murine detrusor muscles mediated by PDGFR?+ interstitial cells. J Physiol 592:1283-93
Sanders, Kenton M; Ward, Sean M; Koh, Sang Don (2014) Interstitial cells: regulators of smooth muscle function. Physiol Rev 94:859-907
Drumm, Bernard T; Koh, Sang Don; Andersson, Karl-Erik et al. (2014) Calcium signalling in Cajal-like interstitial cells of the lower urinary tract. Nat Rev Urol 11:555-64