About 17% of the US population suffers from overactive bladder (OAB) and the associated economic cost is more than $26 billion per year. OAB is a poorly understood disorder characterized by increased urinary bladder smooth muscle (UBSM) contractility. In experimental animals, the large-conductance voltage-gated and Ca2+- activated K+ (BK) channel is a key regulator of UBSM membrane excitability and contractility. In general, inhibition of these ion channels leads to increased membrane excitability and contractility, whereas their activation hyperpolarizes the membrane and decreases contractility. However, the BK channel function and regulation in human UBSM is unknown. Our basic science research group, in collaboration with clinical scientists, is in a unique position to regularly utilize human UBSM tissues from donor patients to study BK channel function in humans and correlate the basic science findings with the clinical and urodynamic profile of the patients. Our long-term goal is to understand the mechanisms that regulate human UBSM BK channels under normal physiological conditions and to develop novel therapeutic strategies to control OAB. The objective of this application is to elucidate the physiological role and regulatory mechanisms of the BK channel in human UBSM contractility under normal physiological conditions. We will test the novel hypothesis that the BK channel determines the myogenic activity of human UBSM and it is regulated by cholinergic, 2- adrenergic, and differential Ca2+ signals with the following Aims:
Aim 1. Elucidate the role of Ca2+ in the regulation of the BK channel in human UBSM myogenic activity;
Aim 2. Elucidate the functional link between 2-adrenoceptors (2-ARs) and BK channels in UBSM;
and Aim 3. Elucidate the functional link between muscarinic (M2 and M3) receptors and BK channels in UBSM. We will employ a combined approach, using state-of-the-art techniques, to determine the role of BK channels and their regulatory mechanisms in UBSM function from single molecules and isolated cells to intact tissue and the whole organism. Our team has the advantage of using full-thickness human UBSM tissues from open surgeries, which allows us to conduct advanced patch-clamp electrophysiology, functional studies on human UBSM contractility, and molecular biology experiments simultaneously. Thus, we can identify channel regulatory proteins, and then correlate BK channel activity with human UBSM contractility properties. Our research team's basic science and clinical expertise may lead to important translational observations. The proposed studies are expected to provide novel insights on BK channel function and regulation by cholinergic, 2-adrenergic, and Ca2+ signals in human UBSM. The results will have a significant impact on urological research with a strong potential to provide novel therapeutic approaches to help a large population of patients suffering from OAB.

Public Health Relevance

Urinary bladder dysfunction is a major health issue in the US. Overactive bladder and related urinary incontinence are poorly understood disorders and effective therapeutic agents to control these conditions are lacking. Our basic science research group in collaboration with clinical scientists uses state-of-the-art techniques at the molecular, cellular, and tissue levels, to determine the role of cell membrane potassium ion channels as novel therapeutic targets to control urinary bladder dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084284-04
Application #
8322549
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$310,921
Indirect Cost
$96,493
Name
University of South Carolina at Columbia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Xin, Wenkuan; Li, Ning; Fernandes, Vitor S et al. (2016) Constitutively active PKA regulates neuronal acetylcholine release and contractility of guinea pig urinary bladder smooth muscle. Am J Physiol Renal Physiol 310:F1377-84
Xin, Wenkuan; Li, Ning; Fernandes, Vitor S et al. (2016) BK channel regulation by phosphodiesterase type 1: a novel signaling pathway controlling human detrusor smooth muscle function. Am J Physiol Renal Physiol 310:F994-9
Hanna-Mitchell, Ann T; Robinson, Dudley; Cardozo, Linda et al. (2016) Do we need to know more about the effects of hormones on lower urinary tract dysfunction? ICI-RS 2014. Neurourol Urodyn 35:299-303
Fernandes, Vítor S; Xin, Wenkuan; Petkov, Georgi V (2015) Novel mechanism of hydrogen sulfide-induced guinea pig urinary bladder smooth muscle contraction: role of BK channels and cholinergic neurotransmission. Am J Physiol Cell Physiol 309:C107-16
Provence, Aaron; Hristov, Kiril L; Parajuli, Shankar P et al. (2015) Regulation of Guinea Pig Detrusor Smooth Muscle Excitability by 17β-Estradiol: The Role of the Large Conductance Voltage- and Ca2+-Activated K+ Channels. PLoS One 10:e0141950
Parajuli, Shankar P; Hristov, Kiril L; Cheng, Qiuping et al. (2015) Functional link between muscarinic receptors and large-conductance Ca2+ -activated K+ channels in freshly isolated human detrusor smooth muscle cells. Pflugers Arch 467:665-75
Provence, Aaron; Malysz, John; Petkov, Georgi V (2015) The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility. J Pharmacol Exp Ther 354:290-301
Xin, Wenkuan; Li, Ning; Cheng, Qiuping et al. (2014) Constitutive PKA activity is essential for maintaining the excitability and contractility in guinea pig urinary bladder smooth muscle: role of the BK channel. Am J Physiol Cell Physiol 307:C1142-50
Xin, Wenkuan; Li, Ning; Cheng, Qiuping et al. (2014) BK channel-mediated relaxation of urinary bladder smooth muscle: a novel paradigm for phosphodiesterase type 4 regulation of bladder function. J Pharmacol Exp Ther 349:56-65
Petkov, Georgi V (2014) Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology. Am J Physiol Regul Integr Comp Physiol 307:R571-84

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