Urinary incontinence has devastating lifestyle effects on at least 13 million Americans, of whom 85% are women, and is a major financial burden on the health care system. Yet, the basic mechanism of the regulation urinary bladder smooth muscle (UBSM) contractility, the control of intracellular Ca2+ and membrane excitability, are poorly understood. The role of UBSM is unique in that it must regulate tone during filling, similar to arterial smooth muscle, and yet when full, contracts forcefully, similar to cardiac muscle. This proposal is based on several major advancements in understanding of Ca2+ regulation in arterial smooth muscle and cardiac muscle, including the measurement of elementary Ca2+ release events (""""""""Ca2+ sparks"""""""") caused by opening of ryanodine-sensitive Ca2+ release (RyR) channels in the sarcoplasmic reticulum (SR). The application proposes that Ca2+ sparks have a novel antagonistic role in the regulation of UBSM excitability and contractility: Ca2+ sparks contribute Ca2+ for contraction during an action potential and may oppose contractility by limiting Ca2+ entry through activation of Kca channels, which decrease excitability. Specifically, the project will examine the nature of Ca2+ sparks and their subsequent activation of Ca2+-sensitive potassium (Kca) channels (Hypothesis 1), the role of Ca2+ sparks to augment global Ca2+ transients during an action potential to enhance contractility (Hypothesis 2A), the role of Ca2+ sparks to limit Ca2+ entry and SR Ca2+ release through shortening the action potential and hyperpolarizing the membrane potential by activation of Kca channels (Hypotheses 2B,C). Further, the proposal will explore the novel idea that frequency and amplitude modulation of Ca2+ sparks and Kca channel currents is a mechanism by which cholinergic stimulation affects UBSM excitability and contractility (Hypothesis 3). Finally, the effort will explore the idea that stretch of UBSM cells differentially affects the antagonistic actions of Ca2+ sparks on global and Kca channels (Hypothesis 4). The proposed study should significantly deepen our understanding of the regulation of UBSM function, and provide new therapeutic targets that may be unique for urinary bladder.
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