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.
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