Liberated PKA Catalytic Subunits Associate with the Membrane via Myristoylation to Preferentially Phosphorylate Membrane Substrates

Abstract

Summary: 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. : The catalytic subunit of protein kinase A (PKA-C) is thought to remain in the cytosol when activated. Tillo et al. modify this view by showing that, upon activation in neurons, PKA-C becomes liberated from the regulatory subunit to associate with the membrane via myristoylation, where it preferentially phosphorylates membrane substrates. Keywords: cAMP-dependent kinase, PKA, myristoylation, activation-dependent membrane association, diffusion, mobility, synaptic plasticity, AMPA/NMDA current radio, mEPSC