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首页> 外文期刊>Journal of Cardiovascular Development and Disease >Phosphodiesterases 3 and 4 Differentially Regulate the Funny Current, I f , in Mouse Sinoatrial Node Myocytes
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Phosphodiesterases 3 and 4 Differentially Regulate the Funny Current, I f , in Mouse Sinoatrial Node Myocytes

机译：磷酸二酯酶3和4差异调节小鼠窦房结肌细胞中的滑稽电流I f。

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Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3′,5′-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac “funny current” (I f ) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. I f is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage-dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them. PKA activity is required for signaling between β adrenergic receptors (βARs) and HCN channels in SAMs but the mechanism that constrains cAMP signaling to a PKA-dependent pathway is unknown. Phosphodiesterases (PDEs) hydrolyze cAMP and form cAMP signaling domains in other types of cardiomyocytes. Here we examine the role of PDEs in regulation of I f in SAMs. I f was recorded in whole-cell voltage-clamp experiments from acutely-isolated mouse SAMs in the absence or presence of PDE and PKA inhibitors, and before and after βAR stimulation. General PDE inhibition caused a PKA-independent depolarizing shift in the midpoint activation voltage (V 1/2 ) of I f at rest and removed the requirement for PKA in βAR-to-HCN signaling. PDE4 inhibition produced a similar PKA-independent depolarizing shift in the V 1/2 of I f at rest, but did not remove the requirement for PKA in βAR-to-HCN signaling. PDE3 inhibition produced PKA-dependent changes in I f both at rest and in response to βAR stimulation. Our results suggest that PDE3 and PDE4 isoforms create distinct cAMP signaling domains that differentially constrain access of cAMP to HCN channels and establish the requirement for PKA in signaling between βARs and HCN channels in SAMs.
机译：在静止和交感战斗或飞行反应期间的心脏起搏取决于窦房结肌细胞（SAMs）中的cAMP（3'，5'-环腺苷一磷酸）信号。心脏“有趣电流”（I f）是对SAM进行起搏的cAMP敏感效应子。 I f由超极化激活的环状核苷酸敏感（HCN）通道产生。 HCN通道的电压依赖性门控由cAMP增强，cAMP通过直接与通道结合或激活cAMP依赖性蛋白激酶（PKA）使其磷酸化来发挥作用。在SAM中，β肾上腺素能受体（βARs）和HCN通道之间的信号传导需要PKA活性，但将cAMP信号传导限制为PKA依赖性途径的机制尚不清楚。磷酸二酯酶（PDE）水解cAMP并在其他类型的心肌细胞中形成cAMP信号域。在这里，我们研究了PDE在SAM中I f调控中的作用。在不存在或存在PDE和PKA抑制剂的情况下以及在βAR刺激之前和之后，从急性分离的小鼠SAM的全细胞电压钳实验中记录了If。一般的PDE抑制导致静止时I f的中点激活电压（V 1/2）的PKA独立去极化移位，并消除了βAR到HCN信号中对PKA的要求。 PDE4抑制在静止时I f的V 1/2中产生类似的独立于PKA的去极化位移，但并未消除βAR到HCN信号中对PKA的要求。 PDE3抑制在静息时和响应βAR刺激后均会产生IKA依赖PKA的变化。我们的结果表明，PDE3和PDE4同工型创建了不同的cAMP信号域，从而差异性地限制了cAMP对HCN通道的访问，并建立了在SAM中βAR和HCN通道之间的信号传递中对PKA的要求。

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