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首页> 外文期刊>The FEBS journal >Inducible knockout mutagenesis reveals compensatory mechanisms elicited by constitutive BK channel deficiency in overactive murine bladder
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Inducible knockout mutagenesis reveals compensatory mechanisms elicited by constitutive BK channel deficiency in overactive murine bladder

机译：诱导性敲除诱变揭示了过度活动的小鼠膀胱中本构性BK通道缺乏引起的补偿机制

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摘要

The large-conductance, voltage-dependent and Ca(2+)-dependent K(+) (BK) channel links membrane depolarization and local increases in cytosolic free Ca(2+) to hyperpolarizing K(+) outward currents, thereby controlling smooth muscle contractility. Constitutive deletion of the BK channel in mice (BK(-/-)) leads to an overactive bladder associated with increased intravesical pressure and frequent micturition, which has been revealed to be a result of detrusor muscle hyperexcitability. Interestingly, time-dependent and smooth muscle-specific deletion of the BK channel (SM-BK(-/-)) caused a more severe phenotype than displayed by constitutive BK(-/-) mice, suggesting that compensatory pathways are active in the latter. In detrusor muscle of BK(-/-) but not SM-BK(-/-) mice, we found reduced L-type Ca(2+) current density and increased expression of cAMP kinase (protein kinase A; PKA), as compared with control mice. Increased expression of PKA in BK(-/-) mice was accompanied by enhanced beta-adrenoceptor/cAMP-mediated suppression of contractions by isoproterenol. This effect was attenuated by about 60-70% in SM-BK(-/-) mice. However, the Rp isomer of adenosine-3',5'-cyclic monophosphorothioate, a blocker of PKA, only partially inhibited enhanced cAMP signaling in BK(-/-) detrusor muscle, suggesting the existence of additional compensatory pathways. To this end, proteome analysis of BK(-/-) urinary bladder tissue was performed, and revealed additional compensatory regulated proteins. Thus, constitutive and inducible deletion of BK channel activity unmasks compensatory mechanisms that are relevant for urinary bladder relaxation.
机译：大电导，电压依赖和Ca（2+）依赖的K（+）（BK）通道链接膜去极化和胞浆游离Ca（2+）局部增加到超极化K（+）向外电流，从而控制平滑肌肉收缩力。小鼠（BK（-/-））中BK通道的组成性缺失会导致膀胱过度活动症，并伴有膀胱内压力增加和频繁排尿，这已被证明是逼尿肌过度兴奋的结果。有趣的是，BK通道（SM-BK（-/-））的时间依赖性和平滑肌特异性缺失导致的表型比本构性BK（-/-）小鼠更严重，这表明补偿性途径在BK通道中很活跃。后者。在逼肌的BK（-/-），而不是SM-BK（-/-）小鼠中，我们发现L型Ca（2+）电流密度降低，而cAMP激酶（蛋白激酶A; PKA）的表达增加与对照小鼠相比。 BK（-/-）小鼠中PKA表达的增加伴随着增强的β-肾上腺素受体/ cAMP介导的异丙肾上腺素抑制收缩。在SM-BK（-/-）小鼠中，这种作用减弱了约60-70％。但是，PKA的阻断剂腺苷3'，5'-环一硫代磷酸酯的Rp异构体仅部分抑制BK（-/-）逼尿肌中cAMP信号的增强，表明存在其他补偿途径。为此，进行了BK（-/-）膀胱组织的蛋白质组分析，并揭示了其他补偿性调节蛋白。因此，BK通道活性的组成性和诱导性缺失揭示了与膀胱松弛相关的补偿机制。

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