Xiong Wei-Hong, Qin Maozhen, Zhong Haining
Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
bioRxiv. 2024 Aug 20:2023.09.05.556437. doi: 10.1101/2023.09.05.556437.
Protein kinase A (PKA) plays essential roles in diverse cellular functions. However, the spatiotemporal dynamics of endogenous PKA upon activation remain debated. The classical model predicts that PKA catalytic subunits dissociate from regulatory subunits in the presence of cAMP, whereas a second model proposes that catalytic subunits remain associated with regulatory subunits following physiological activation. Here we report that different PKA subtypes, as defined by the regulatory subunit, exhibit distinct subcellular localization at rest in CA1 neurons of cultured hippocampal slices. Nevertheless, when all tested PKA subtypes are activated by norepinephrine, presumably via the β-adrenergic receptor, catalytic subunits translocate to dendritic spines but regulatory subunits remain unmoved. These differential spatial dynamics between the subunits indicate that at least a significant fraction of PKA dissociates. Furthermore, PKA-dependent regulation of synaptic plasticity and transmission can be supported only by wildtype, dissociable PKA, but not by inseparable PKA. These results indicate that endogenous PKA regulatory and catalytic subunits dissociate to achieve PKA function in neurons.
蛋白激酶A（PKA）在多种细胞功能中发挥着重要作用。然而，内源性PKA激活后的时空动态仍存在争议。经典模型预测，在cAMP存在的情况下，PKA催化亚基会与调节亚基解离，而另一种模型则提出，生理激活后催化亚基仍与调节亚基结合。在此，我们报告，由调节亚基定义的不同PKA亚型，在培养的海马切片CA1神经元静息时表现出不同的亚细胞定位。然而，当所有测试的PKA亚型被去甲肾上腺素激活时，推测是通过β-肾上腺素能受体，催化亚基会转移到树突棘，但调节亚基仍保持不动。亚基之间这些不同的空间动态表明，至少相当一部分PKA会解离。此外，只有野生型、可解离的PKA才能支持PKA依赖的突触可塑性和传递调节，而不可分离的PKA则不能。这些结果表明，内源性PKA调节亚基和催化亚基会解离以在神经元中实现PKA功能。
