AKAP79 enables calcineurin to directly suppress protein kinase A activity.
AKAP79 enables calcineurin to directly suppress protein kinase A activity.
复制标题
AKAP 79使钙调磷酸酶能够直接抑制蛋白激酶A活性。
DOI：
10.7554/elife.68164
复制
发表时间：
2021-10-06
期刊：
影响因子：
7.7
通讯作者：
Gold MG
中科院分区：
文献类型：
--
作者：
Church TW;Tewatia P;Hannan S;Antunes J;Eriksson O;Smart TG;Hellgren Kotaleski J;Gold MG
第二信使cAMP和Ca 2+之间的相互作用是动态细胞过程的标志。一个共同的基序是Ca2+敏感性磷酸酶钙调神经磷酸酶和主要的cAMP受体蛋白激酶A（PKA）的对立。钙调磷酸酶使PKA引发的位点去磷酸化，从而引起包括突触长期抑制（LTD）在内的变化。AKAP 79通过锚定PKA和钙调磷酸酶串联支持这种类型的信号传导。在这项研究中，我们发现AKAP 79增加II型PKA调节亚基的钙调磷酸酶去磷酸化速率一个数量级。由动力学模型支持的荧光PKA活性报告基因测定显示了AKAP 79增强的钙调磷酸酶活性如何通过增加PKA催化亚基捕获率来抑制PKA而不改变cAMP水平。海马神经元的实验表明，这种机制有助于LTD.PKA调节的非典型模式可能是许多其他细胞过程的基础。
Interplay between the second messengers cAMP and Ca2+ is a hallmark of dynamic cellular processes. A common motif is the opposition of the Ca2+-sensitive phosphatase calcineurin and the major cAMP receptor, protein kinase A (PKA). Calcineurin dephosphorylates sites primed by PKA to bring about changes including synaptic long-term depression (LTD). AKAP79 supports signaling of this type by anchoring PKA and calcineurin in tandem. In this study, we discovered that AKAP79 increases the rate of calcineurin dephosphorylation of type II PKA regulatory subunits by an order of magnitude. Fluorescent PKA activity reporter assays, supported by kinetic modeling, show how AKAP79-enhanced calcineurin activity enables suppression of PKA without altering cAMP levels by increasing PKA catalytic subunit capture rate. Experiments with hippocampal neurons indicate that this mechanism contributes toward LTD. This non-canonical mode of PKA regulation may underlie many other cellular processes.