Dopamine D2 and Adenosine A2A Receptors Regulate NMDA-mediated Excitation in Accumbens Neurons Through A2A-D2 Receptor Heteromerization

Neuropsychopharmacology. 2009 Mar;34(4):972-86. doi: 10.1038/npp.2008.144. Epub 2008 Sep 17.

Abstract

Bursting activity of striatal medium spiny neurons results from membrane potential oscillations between a down- and an upstate that could be regulated by G-protein-coupled receptors. Among these, dopamine D(2) and adenosine A(2A) receptors are highly enriched in striatal neurons and exhibit strong interactions whose physiological significance and molecular mechanisms remain partially unclear. More particularly, respective involvements of common intracellular signaling cascades and A(2A)-D(2) receptor heteromerization remain unknown. Here we show, by performing perforated-patch-clamp recordings on brain slices and loading competitive peptides, that D(2) and A(2A) receptors regulate the induction by N-methyl-D-aspartate of a depolarized membrane potential plateau through mechanisms relying upon specific protein-protein interactions. Indeed, D(2) receptor activation abolished transitions between a hyperpolarized resting potential and a depolarized plateau potential by regulating the Ca(V)1.3a calcium channel activity through interactions with scaffold proteins Shank1/3. Noticeably, A(2A) receptor activation had no effect per se but fully reversed the effects of D(2) receptor activation through a mechanism in which A(2A)-D(2) receptors heteromerization is strictly mandatory, demonstrating therefore a first direct physiological relevance of these heteromers. Our results show that membrane potential transitions and firing patterns in striatal neurons are tightly controlled by D(2) and A(2A) receptors through specific protein-protein interactions including A(2A)-D(2) receptors heteromerization.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Calcium Channels, L-Type / metabolism
  • In Vitro Techniques
  • Membrane Potentials / physiology
  • Mice
  • Mice, Knockout
  • N-Methylaspartate / metabolism*
  • Nerve Tissue Proteins
  • Neurons / metabolism*
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / metabolism*
  • Patch-Clamp Techniques
  • Presynaptic Terminals / metabolism
  • Protein Multimerization
  • Rats
  • Rats, Wistar
  • Receptors, Adenosine A2 / metabolism*
  • Receptors, Dopamine D2 / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Calcium Channels, L-Type
  • Nerve Tissue Proteins
  • Receptors, Adenosine A2
  • Receptors, Dopamine D2
  • Shank1 protein, rat
  • Shank3 protein, rat
  • N-Methylaspartate