Protein kinase C depresses cardiac myocyte power output and attenuates myofilament responses induced by protein kinase A.
Protein kinase C depresses cardiac myocyte power output and attenuates myofilament responses induced by protein kinase A.
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DOI：
10.1007/s10974-012-9294-9
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发表时间：
2012-12
影响因子：
2.7
通讯作者：
McDonald, Kerry S.
中科院分区：
文献类型：
--
作者：
Hinken, Aaron C.;Hanft, Laurin M.;Scruggs, Sarah B.;Sadayappan, Sakthivel;Robbins, Jeffery;Solaro, R. John;McDonald, Kerry S.
被 G 蛋白偶联受体激动剂激活后，蛋白激酶 C (PKC) 通过细胞内靶标（包括肌丝蛋白心肌肌钙蛋白 I (cTnI) 和心肌肌球蛋白结合蛋白 C (cMyBP-C)）的磷酸化来调节心肌细胞功能。由于 PKC 磷酸化已被证明可降低肌原纤维 ATP 酶活性，因此我们假设 cTnI 和 cMyBP-C 的 PKC 磷酸化将降低肌细胞的功率输出，此外，还会减弱对蛋白激酶 A (PKA) 介导的磷酸化反应的功率升高。我们比较了用 PKC 催化亚基处理前后大鼠皮心肌细胞的等长力和发电能力。 PKC 增加了 cMyBP-C 和 cTnI 的磷酸化水平，并降低了最大 Ca2+ 激活力和 Ca2+ 力敏感性。此外，在次最大 Ca2+ 激活过程中，PKC 使功率输出降低了 62%，这是由于力下降和负载缩短速度减慢造成的，因为即使 PKC 前后的力水平匹配，功率下降仍然持续。此外，PKC 减弱了 PKA 对 cTnI 的磷酸化，减少了 PKA 诱导的自发振荡收缩，并减少了 PKA 介导的肌细胞能量升高。为了测试改变的细丝功能是否在这些收缩变化中发挥重要作用，我们使用来自转基因动物的肌细胞制剂研究了慢性cTnI假磷酸化对肌丝功能的影响，其中仅PKA磷酸化位点（Ser-23/Ser-24）（PP）或PKA和PKC磷酸化位点（Ser-23/Ser-24/Ser-43/Ser-45/T-144） (All-P)被天冬氨酸取代。 All-P 转基因小鼠的心肌细胞表现出最大力、力的 Ca2+ 敏感性和功率的降低。通过原位压力-体积测量确定，在 All-P 小鼠的心脏中观察到发电能力同样降低。这些结果表明 PKC 介导的 cTnI 磷酸化在抑制收缩力中起主导作用，因此，PKC 同工酶活性增加可能导致心力衰竭进展过程中表现出的适应不良行为。
Following activation by G-protein-coupled receptor agonists, protein kinase C (PKC) modulates cardiac myocyte function by phosphorylation of intracellular targets including myofilament proteins cardiac troponin I (cTnI) and cardiac myosin binding protein C (cMyBP-C). Since PKC phosphorylation has been shown to decrease myofibril ATPase activity, we hypothesized that PKC phosphorylation of cTnI and cMyBP-C will lower myocyte power output and, in addition, attenuate the elevation in power in response to protein kinase A (PKA)-mediated phosphorylation. We compared isometric force and power generating capacity of rat skinned cardiac myocytes before and after treatment with the catalytic subunit of PKC. PKC increased phosphorylation levels of cMyBP-C and cTnI and decreased both maximal Ca2+ activated force and Ca2+ sensitivity of force. Moreover, during submaximal Ca2+ activations PKC decreased power output by 62 %, which arose from both the fall in force and slower loaded shortening velocities since depressed power persisted even when force levels were matched before and after PKC. In addition, PKC blunted the phosphorylation of cTnI by PKA, reduced PKA-induced spontaneous oscillatory contractions, and diminished PKA-mediated elevations in myocyte power. To test whether altered thin filament function plays an essential role in these contractile changes we investigated the effects of chronic cTnI pseudo-phosphorylation on myofilament function using myocyte preparations from transgenic animals in which either only PKA phosphorylation sites (Ser-23/Ser-24) (PP) or both PKA and PKC phosphorylation sites (Ser-23/Ser-24/Ser-43/Ser-45/T-144) (All-P) were replaced with aspartic acid. Cardiac myocytes from All-P transgenic mice exhibited reductions in maximal force, Ca2+ sensitivity of force, and power. Similarly diminished power generating capacity was observed in hearts from All-P mice as determined by in situ pressure–volume measurements. These results imply that PKC-mediated phosphorylation of cTnI plays a dominant role in depressing contractility, and, thus, increased PKC isozyme activity may contribute to maladaptive behavior exhibited during the progression to heart failure.
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影响因子：
4.8
作者：
Jideama, NM;Noland, TA;Kuo, JF
通讯作者：
Kuo, JF
影响因子：
20.1
作者：
Hidalgo C;Hudson B;Bogomolovas J;Zhu Y;Anderson B;Greaser M;Labeit S;Granzier H
通讯作者：
Granzier H
影响因子：
20.1
作者：
Kirk, Jonathan A.;MacGowan, Guy A.;Shroff, Sanjeev G.
通讯作者：
Shroff, Sanjeev G.
影响因子：
20.1
作者：
Herron, TJ;Korte, FS;McDonald, KS
通讯作者：
McDonald, KS
影响因子：
82.9
作者：
Braz, JC;Gregory, K;Molkentin, JD
通讯作者：
Molkentin, JD