Braz Julian C, Gregory Kimberly, Pathak Anand, Zhao Wen, Sahin Bogachan, Klevitsky Raisa, Kimball Thomas F, Lorenz John N, Nairn Angus C, Liggett Stephen B, Bodi Ilona, Wang Su, Schwartz Arnold, Lakatta Edward G, DePaoli-Roach Anna A, Robbins Jeffrey, Hewett Timothy E, Bibb James A, Westfall Margaret V, Kranias Evangelia G, Molkentin Jeffery D
Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Nat Med. 2004 Mar;10(3):248-54. doi: 10.1038/nm1000. Epub 2004 Feb 15.
The protein kinase C (PKC) family of serine/threonine kinases functions downstream of nearly all membrane-associated signal transduction pathways. Here we identify PKC-alpha as a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. Hearts of Prkca-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing Prkca are hypocontractile. Adenoviral gene transfer of dominant-negative or wild-type PKC-alpha into cardiac myocytes enhances or reduces contractility, respectively. Mechanistically, modulation of PKC-alpha activity affects dephosphorylation of the sarcoplasmic reticulum Ca(2+) ATPase-2 (SERCA-2) pump inhibitory protein phospholamban (PLB), and alters sarcoplasmic reticulum Ca(2+) loading and the Ca(2+) transient. PKC-alpha directly phosphorylates protein phosphatase inhibitor-1 (I-1), altering the activity of protein phosphatase-1 (PP-1), which may account for the effects of PKC-alpha on PLB phosphorylation. Hypercontractility caused by Prkca deletion protects against heart failure induced by pressure overload, and against dilated cardiomyopathy induced by deleting the gene encoding muscle LIM protein (Csrp3). Deletion of Prkca also rescues cardiomyopathy associated with overexpression of PP-1. Thus, PKC-alpha functions as a nodal integrator of cardiac contractility by sensing intracellular Ca(2+) and signal transduction events, which can profoundly affect propensity toward heart failure.
丝氨酸/苏氨酸激酶的蛋白激酶C（PKC）家族在几乎所有与膜相关的信号转导途径下游发挥作用。在此，我们确定PKC-α是心肌细胞中心脏收缩力和Ca(2+)处理的基本调节因子。Prkca基因缺陷小鼠的心脏收缩力增强，而过度表达Prkca的转基因小鼠的心脏收缩力减弱。将显性负性或野生型PKC-α通过腺病毒基因转移至心肌细胞中，分别增强或降低了收缩力。从机制上讲，PKC-α活性的调节影响肌浆网Ca(2+)ATP酶-2（SERCA-2）泵抑制蛋白受磷蛋白（PLB）的去磷酸化，并改变肌浆网Ca(2+)的负载和Ca(2+)瞬变。PKC-α直接磷酸化蛋白磷酸酶抑制剂-1（I-1），改变蛋白磷酸酶-1（PP-1）的活性，这可能解释了PKC-α对PLB磷酸化的影响。Prkca缺失引起的收缩力增强可预防压力超负荷诱导的心力衰竭以及因缺失编码肌肉LIM蛋白（Csrp3）的基因而导致的扩张型心肌病。Prkca的缺失还可挽救与PP-1过表达相关的心肌病。因此，PKC-α通过感知细胞内Ca(2+)和信号转导事件，作为心脏收缩力的节点整合器发挥作用，这可深刻影响心力衰竭的倾向。
