Beta-adrenergic relaxation of urinary bladder smooth muscle

描述(由申请人提供)： 膀胱有两个主要功能：储存和排尿。膀胱平滑肌(UBSM)的收缩和松弛对这些任务至关重要。交感神经在充盈过程中通过刺激(-肾上腺素能受体)维持膀胱的松弛。然而，(-肾上腺素能)刺激松弛UBSM的确切生理机制尚不清楚。 尿失禁是一种常见的泌尿生殖系统疾病，可导致危及生命的肾脏问题。最普遍的尿失禁类型是急迫性尿失禁，这是UBSM收缩增加的结果。有证据表明，UBSM受体或离子通道的缺陷，如大电导钙激活K+(BK)通道和小电导钙激活K+(SK)通道，可能是某些形式的膀胱功能障碍的基础，包括急迫性尿失禁。我们最近证实，BK通道可以在肾上腺素能刺激下被激活，通过钙依赖的机制促进UBSM的松弛(Petkov&Nelson，2005，American Journal of Physiology)。 本项目将致力于阐明(-肾上腺素能刺激促进UBSM松弛的细胞和分子机制。总体假设是，P-肾上腺素能刺激通过BK和SK通道、肌浆网(SR)钙离子和尿路上皮等机制起到松弛UBSM的作用。 具体目标1将阐明(-肾上腺素能刺激激活BK通道的机制； 具体目标2将阐明肌浆网(SR)钙离子在肾上腺素能UBSM松弛中的作用； 具体目标3将阐明SK通道和尿路上皮在UBSM-肾上腺素能松弛中的作用。 我们将使用一种综合的方法，结合电生理、钙成像、分子生物学以及体内和体外对正常和基因工程小鼠膀胱收缩功能的研究，以解决UBSM功能的-肾上腺素能调节这一根本问题。 建立UBSM(肾上腺素能松弛)的确切分子机制将为治疗尿失禁提供新的潜在治疗靶点

DESCRIPTION (provided by applicant): The urinary bladder has two major functions; storage and voiding of urine. Contraction and relaxation of the urinary bladder smooth muscle (UBSM) is crucial to these tasks. Sympathetic nerves maintain relaxation of the bladder during filling via stimulation of (-adrenoceptors. However, the exact physiological mechanisms by which (-adrenergic stimulation relaxes UBSM is unknown. Urinary incontinence is a common urogenital disease that can lead to life-threatening kidney problems. The most widespread type of incontinence, urge incontinence, is a result of increased UBSM contractions. Evidence suggests that defects in UBSM receptors or ion channels, such as the large conductance Ca2+-activated K+ (BK) channel and the small conductance Ca2+-activated K+ (SK) channel may underlie certain forms of urinary bladder dysfunction, including urge incontinence. We recently demonstrated that BK channel can be activated upon (-adrenergic stimulation to promote UBSM relaxation via a Ca2+-dependent mechanism (Petkov & Nelson, 2005, American Journal of Physiology). This project will focus on elucidating the cellular and molecular mechanisms by which (-adrenergic stimulation promotes UBSM relaxation. The overall hypothesis is that P-adrenergic stimulation relaxes UBSM via mechanisms, involving BK and SK channels, sarcoplasmic reticulum (SR) Ca2+ and urothelium. Specific aim 1 will elucidate the mechanisms by which (-adrenergic stimulation activates BK channels; Specific aim 2 will elucidate the role of sarcoplasmic reticulum (SR) Ca2+ in (-adrenergic UBSM relaxation; Specific aim 3 will elucidate the roles of SK channels and the urothelium in (-adrenergic relaxation of UBSM. We will use an integrated approach, combining electrophysiological, Ca2+ imaging, molecular biology, as well as in vivo and in vitro functional studies on bladder contractility in normal and genetically engineered mice to address the fundamental issue of (-adrenergic regulation of UBSM function. Establishing the exact molecular mechanisms of UBSM (-adrenergic relaxation will provide new potential therapeutic targets for treating urinary incontinence