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J Biol Chem. 2016 Oct 28;291(44):23257-23267. Epub 2016 Sep 7.

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.

Author information

1
From the Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
2
From the Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029 Susana.neves@mssm.edu.

Abstract

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

PMID:
27605670
PMCID:
PMC5087742
DOI:
10.1074/jbc.M116.749747
[Indexed for MEDLINE]
Free PMC Article

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