Beta-adrenergic relaxation of urinary bladder smooth muscle

膀胱有两个主要功能：储存和排尿。尿液的收缩和松弛 膀胱平滑肌(UBSM)对这些任务至关重要。交感神经维持膀胱的松弛 通过刺激(3-肾上腺素能受体)充盈。然而，P-肾上腺素能的确切生理机制 刺激松弛UBSM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。最多的 广泛的尿失禁类型，即急迫性尿失禁，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 电导钙激活的K+(SK)通道可能是某些形式的膀胱功能障碍的基础，包括冲动 大小便失禁。我们最近证实，BK通道可以在刺激P-肾上腺素能时被激活，从而促进 通过钙依赖机制的UBSM松弛(Petkov&Nelson，2005，美国生理学杂志)。 本项目将致力于阐明P-肾上腺素能刺激的细胞和分子机制。 促进UBSM松弛。总体假设是，P-肾上腺素能刺激通过 机制涉及BK和SK通道、肌浆网(SR)钙离子和尿路上皮。 具体目标1将阐明P-肾上腺素能刺激激活BK通道的机制； 特异性目标2阐明肌浆网(SR)钙离子在P-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的P-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、分子生物学以及在 正常小鼠和基因工程小鼠膀胱收缩功能的体内和体外功能研究 UBSM功能的P-肾上腺素能调节的基本问题。 建立UBSM P-肾上腺素能松弛的确切分子机制将提供新的潜力 治疗尿失禁的治疗靶点。

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 (3-adrenoceptors. However, the exact physiological mechanisms by which P-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 P-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 P-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 P-adrenergic stimulation activates BK channels; Specific aim 2 will elucidate the role of sarcoplasmic reticulum (SR) Ca2+ in P-adrenergic UBSM relaxation; Specific aim 3 will elucidate the roles of SK channels and the urothelium in P-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 P-adrenergic regulation of UBSM function. Establishing the exact molecular mechanisms of UBSM P-adrenergic relaxation will provide new potential therapeutic targets for treating urinary incontinence.