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.
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.
From the Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
Roy S
RS
Song
From the Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
Rosa
R
Tolentino
From the Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
Eric A
EA
Sobie
From the Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029 Susana.neves@mssm.edu.
Susana R
SR
Neves-Zaph
D000494:Allosteric Regulation; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000235:genetics* / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000235:genetics* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism*
D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D004298:Dopamine
AMPA receptor (AMPAR); GluA1; PDE1; PDE2; cAMP; cGMP; dopamine; phosphodiesterases; trafficking