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Signalling to contractile proteins by muscarinic and purinergic pathways in neurally stimulated bladder smooth muscle

机译:通过神经刺激的膀胱平滑肌中的毒蕈碱和嘌呤能途径向收缩蛋白发出信号

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摘要

Urinary bladder smooth muscle contraction is triggered by parasympathetic nerves, which release ATP and acetylcholine (ACh) that bind to purinergic and muscarinic receptors, respectively. Neuronal signalling may thus elicit myosin regulatory light chain (RLC) phosphorylation and contraction through the combined, but distinct contributions of these receptors. Both receptors mediate Ca2+ influx whereas muscarinic receptors may also recruit Ca2+-sensitization mechanisms. Using transgenic mice expressing calmodulin sensor myosin light chain kinase (MLCK) in smooth muscles, the effects of suramin/α,β-methyleneATP (α,β-meATP) (purinergic inhibition) or atropine (muscarinic inhibition) on neurally stimulated elevation of [Ca2+]i, MLCK activation, force and phosphorylation of RLC, myosin light chain phosphatase (MLCP) targeting subunit MYPT1 and MLCP inhibitor protein CPI-17 were examined. Electric field stimulation (EFS) increased [Ca2+]i, MLCK activation and concomitant force in a frequency-dependent manner. The dependence of force on [Ca2+]i and MLCK activation decreased with time suggesting increased Ca2+ sensitization in the late contractile phase. RLC and CPI-17 phosphorylation increased upon stimulation with maximal responses at 20 Hz; both responses were attenuated by atropine, but only RLC phosphorylation was inhibited by suramin/α,β-meATP. Antagonism of purinergic receptors suppressed maximal MLCK activation to a greater extent in the early contractile phase than in the late contractile phase; atropine had the opposite effect. A frequency- and time-dependent increase in MLCK phosphorylation explained the desensitization of MLCK to Ca2+, since MLCK activation declined more rapidly than [Ca2+]i. EFS elicited little or no effect on MYPT1 Thr696 or 850 phosphorylation. Thus, purinergic Ca2+ signals provide the initial activation of MLCK with muscarinic receptors supporting sustained responses. Activation of muscarinic receptors recruits CPI-17, but not MYPT1-mediated Ca2+ sensitization. Furthermore, nerve-released ACh also initiates signalling cascades leading to phosphorylation-dependent desensitization of MLCK.
机译:副交感神经触发膀胱平滑肌收缩,释放分别与嘌呤能和毒蕈碱受体结合的ATP和乙酰胆碱(ACh)。因此,神经元信号传导可通过这些受体的组合但独特的作用引发肌球蛋白调节性轻链(RLC)磷酸化和收缩。两种受体都介导Ca 2 + 流入,而毒蕈碱受体也可能募集Ca 2 + 致敏机制。使用在平滑肌中表达钙调蛋白传感器肌球蛋白轻链激酶(MLCK)的转基因小鼠,苏拉明/α,β-亚甲基ATP(α,β-meATP)(嘌呤能抑制)或阿托品(毒蕈碱抑制)对神经刺激的[[研究了Ca 2+,i MLCK活化,RLC的力和磷酸化,肌球蛋白轻链磷酸酶(MLCP)靶向亚基MYPT1和MLCP抑制剂蛋白CPI-17。电场刺激(EFS)以频率依赖性方式增加[Ca 2 + ] i,MLCK激活和伴随力。力对[Ca 2 + ] i和MLCK活化的依赖性随时间降低,提示在收缩后期Ca 2 + 致敏性增加。刺激后,RLC和CPI-17磷酸化增强,在20 Hz时反应最大。阿托品减弱了两种反应,但苏拉明/α,β-meATP仅抑制了RLC磷酸化。嘌呤能受体的拮抗作用在收缩初期比收缩后期抑制最大的MLCK活化。阿托品具有相反的作用。 MLCK磷酸化的频率和时间依赖性增加解释了MLCK对Ca 2 + 的脱敏作用,因为MLCK的活化作用比[Ca 2 + ] i下降得更快。 EFS对MYPT1 Thr696或850磷酸化几乎没有影响。因此,嘌呤能Ca 2 + 信号通过支持持续反应的毒蕈碱受体提供了MLCK的初始激活。毒蕈碱受体的激活募集CPI-17,但不诱MYPT1介导的Ca 2 + 致敏。此外,神经释放的乙酰胆碱也引发信号级联反应,导致MLCK的磷酸化依赖性脱敏。

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