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

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, Haining Zhong

Research output: Contribution to journalArticle

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)617-629
Number of pages13
JournalCell Reports
Volume19
Issue number3
DOIs
StatePublished - Apr 18 2017

Keywords

  • AMPA/NMDA current radio
  • PKA
  • activation-dependent membrane association
  • cAMP-dependent kinase
  • diffusion
  • mEPSC
  • mobility
  • myristoylation
  • synaptic plasticity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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