Detrusor instability is a major component of urinary bladder dysfunction, including outflow obstruction associated with benign prostate hyperplasia. The goal of this project is to understand the normal physiological regulation of urinary bladder smooth muscle (UBSM) excitability and to apply an experimental model of partial urinary outflow obstruction to address pathophysiological aspects of UBSM function. This proposal focuses on the communication among four key ion channels involved in regulating the excitation-contraction (E-C) coupling process in UBSM: 1) Voltage-dependent calcium channels (VDCC), which mediate the upstroke of the UBSM action potential. 2) Ryanodine-sensitive calcium release channels in the sarcoplasmic reticulum (RyRs), which release Ca2+ in the form of Ca2+ sparks. 3) Large-conductance, voltage/calcium-activated potassium (BK) channels, which mediate membrane repolarization of an action potential. 4) Small-conductance, calcium-activated (SK) channels, which are responsible for the after-hyperpolarization. This work builds on our discovery of Ca2+ sparks and their communication to BK channels in smooth muscle, and elucidation of key molecular components of this process. In an important advancement, we have found that the beta 1-subunit of the BK channel plays a major role by tuning the voltage/Ca2+ -sensitivity of this channel. We provide novel evidence that the BK channel beta 1-subunit and SK channels have profound effects on bladder function; data that point to potassium channel dysfunction as a significant contributor to detrusor instability following obstruction. An integrated approach, combining molecular and electrophysiological studies with functional measures of bladder contractility and cystometric parameters, will be applied using wild-type and genetically engineered mouse models. Our specific objectives are to elucidate the functional communication among VDCCs, RyRs and BK channels in normal and outflow obstructed bladders (Aim 1), to characterize the role of the beta 1-subunit in tuning the Ca2~ and voltage sensitivity of the BK channel (Aim 2), and to defme the roles of SK channels in the regulation of UBSM function (Aim 3). The long-term goal is to develop novel approaches for regulating urinary bladder function, with the main focus being on the therapy of detrusor instability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053832-07
Application #
6784516
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Mullins, Christopher V
Project Start
1998-08-01
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
7
Fiscal Year
2004
Total Cost
$316,588
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Harraz, Osama F; Longden, Thomas A; Dabertrand, Fabrice et al. (2018) Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion. Proc Natl Acad Sci U S A 115:E3569-E3577
Baylie, Rachael; Ahmed, Majid; Bonev, Adrian D et al. (2017) Lack of direct effect of adiponectin on vascular smooth muscle cell BKCa channels or Ca2+ signaling in the regulation of small artery pressure-induced constriction. Physiol Rep 5:
Heppner, Thomas J; Hennig, Grant W; Nelson, Mark T et al. (2017) Rhythmic Calcium Events in the Lamina Propria Network of the Urinary Bladder of Rat Pups. Front Syst Neurosci 11:87
Khavandi, Kaivan; Baylie, Rachael A; Sugden, Sarah A et al. (2016) Pressure-induced oxidative activation of PKG enables vasoregulation by Ca2+ sparks and BK channels. Sci Signal 9:ra100
Nausch, Bernhard; Rode, Frederik; Jørgensen, Susanne et al. (2014) NS19504: a novel BK channel activator with relaxing effect on bladder smooth muscle spontaneous phasic contractions. J Pharmacol Exp Ther 350:520-30
Dunn, Kathryn M; Nelson, Mark T (2014) Neurovascular signaling in the brain and the pathological consequences of hypertension. Am J Physiol Heart Circ Physiol 306:H1-14
Gonzales, Albert L; Yang, Ying; Sullivan, Michelle N et al. (2014) A PLC?1-dependent, force-sensitive signaling network in the myogenic constriction of cerebral arteries. Sci Signal 7:ra49
Sonkusare, Swapnil K; Dalsgaard, Thomas; Bonev, Adrian D et al. (2014) AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. Sci Signal 7:ra66
Mercado, Jose; Baylie, Rachael; Navedo, Manuel F et al. (2014) Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle. J Gen Physiol 143:559-75
Krishnamoorthy, Gayathri; Sonkusare, Swapnil K; Heppner, Thomas J et al. (2014) Opposing roles of smooth muscle BK channels and ryanodine receptors in the regulation of nerve-evoked constriction of mesenteric resistance arteries. Am J Physiol Heart Circ Physiol 306:H981-8

Showing the most recent 10 out of 58 publications