Liberated PKA catalytic subunits associate with the membrane via myristoylation to preferentially phosphorylate membrane substrates.

Cell Reports. 31 Mar 2017, 19(3):617-629. doi: https://doi.org/10.1016/j.celrep.2017.03.070

Shane E. Tillo, Wei-Hong Xiong, Maho Takahashi, Sheng Miao, Adriana L. Andrade, Dale A. Fortin, Guang Yang, Maozhen Qin, Barbara F. Smoody, Philip J. S. Stork, and Haining Zhong.

Abstract
Protein kinase A (PKA) has diverse functions in neurons. At rest, the subcellular localization of PKA is controlled by A-kinase anchoring proteins (AKAPs). However, the dynamics of PKA upon activation remain poorly understood. Here, we report that elevation of cyclic AMP (cAMP) in neuronal dendrites causes a significant percentage of the PKA catalytic subunit (PKA-C) molecules to be released from the regulatory subunit (PKA-R). Liberated PKA-C becomes associated with the membrane via N-terminal myristoylation. This membrane association does not require the interaction between PKA-R and AKAPs. It slows the mobility of PKA-C and enriches kinase activity on the membrane. Membrane-residing PKA substrates are preferentially phosphorylated compared to cytosolic substrates. Finally, the myristoylation of PKA-C is critical for normal synaptic function and plasticity. We propose that activation-dependent association of PKA-C renders the membrane a unique PKA-signaling compartment. Constrained mobility of PKA-C may synergize with AKAP anchoring to determine specific PKA function in neurons.