Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biomedical Engineering, Columbia University, New York, NY, USA.
Cell Rep. 2022 Aug 16;40(7):111203. doi: 10.1016/j.celrep.2022.111203.
In the heart, protein kinase A (PKA) is critical for activating calcium handling and sarcomeric proteins in response to beta-adrenergic stimulation leading to increased myocardial contractility and performance. The catalytic activity of PKA is tightly regulated by regulatory subunits that inhibit the catalytic subunit until released by cAMP binding. Phosphorylation of type II regulatory subunits promotes PKA activation; however, the role of phosphorylation in type I regulatory subunits remain uncertain. Here, we utilize human induced pluripotent stem cell cardiomyocytes (iPSC-CMs) to identify STK25 as a kinase of the type Iα regulatory subunit PRKAR1A. Phosphorylation of PRKAR1A leads to inhibition of PKA kinase activity and increased binding to the catalytic subunit in the presence of cAMP. Stk25 knockout in mice diminishes Prkar1a phosphorylation, increases Pka activity, and augments contractile response to beta-adrenergic stimulation. Together, these data support STK25 as a negative regulator of PKA signaling through phosphorylation of PRKAR1A.
在心脏中，蛋白激酶 A（PKA）对于激活钙处理和肌节蛋白以响应β-肾上腺素能刺激从而增加心肌收缩力和性能至关重要。PKA 的催化活性受到调节亚基的严格调节，这些亚基抑制催化亚基，直到 cAMP 结合释放。II 型调节亚基的磷酸化促进 PKA 激活；然而，I 型调节亚基的磷酸化作用仍不确定。在这里，我们利用人诱导多能干细胞心肌细胞（iPSC-CMs）来鉴定 STK25 是 PRKAR1A 型 Iα 调节亚基的激酶。在 cAMP 存在的情况下，PRKAR1A 的磷酸化导致 PKA 激酶活性的抑制和与催化亚基的结合增加。在小鼠中敲除 Stk25 会减少 Prkar1a 的磷酸化，增加 Pka 活性，并增强对β-肾上腺素能刺激的收缩反应。总之，这些数据支持 STK25 通过磷酸化 PRKAR1A 作为 PKA 信号的负调节剂。
