Cross-regulation of Phosphodiesterase 1 and Phosphodiesterase 2 Activities Controls Dopamine-mediated Striatal α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Trafficking

J Biol Chem. 2016 Oct 28;291(44):23257-23267. doi: 10.1074/jbc.M116.749747. Epub 2016 Sep 7.


Dopamine, a key striatal neuromodulator, increases synaptic strength by promoting surface insertion and/or retention of AMPA receptors (AMPARs). This process is mediated by the phosphorylation of the GluA1 subunit of AMPAR by cyclic nucleotide-dependent kinases, making cyclic nucleotide phosphodiesterases (PDEs) potential regulators of synaptic strength. In this study, we examined the role of phosphodiesterase 2 (PDE2), a medium spiny neuron-enriched and cGMP-activated PDE, in AMPAR trafficking. We found that inhibiting PDE2 resulted in enhancement of dopamine-induced surface GluA1 expression in dopamine receptor 1-expressing medium spiny neurons. Using pharmacological and genetic approaches, we found that inhibition of PDE1 resulted in a decrease in surface AMPAR levels because of the allosteric activation of PDE2. The cross-regulation of PDE1 and PDE2 activities results in counterintuitive control of surface AMPAR expression, making it possible to regulate the directionality and magnitude of AMPAR trafficking.

Keywords: AMPA receptor (AMPAR); GluA1; PDE1; PDE2; cAMP; cGMP; dopamine; phosphodiesterases; trafficking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Corpus Striatum / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / genetics*
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / genetics*
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / metabolism
  • Dopamine / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Protein Transport
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism*


  • Receptors, AMPA
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Dopamine