Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias

Neurobiol Dis. 2017 Dec:108:54-64. doi: 10.1016/j.nbd.2017.08.001. Epub 2017 Aug 18.


N-methyl-d-aspartate receptor (NMDAR) subunit composition strictly commands receptor function and pharmacological responses. Changes in NMDAR subunit composition have been documented in brain disorders such as Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesias (LIDs), where an increase of NMDAR GluN2A/GluN2B subunit ratio at striatal synapses has been observed. A therapeutic approach aimed at rebalancing NMDAR synaptic composition represents a valuable strategy for PD and LIDs. To this, the comprehension of the molecular mechanisms regulating the synaptic localization of different NMDAR subtypes is required. We have recently demonstrated that Rabphilin 3A (Rph3A) is a new binding partner of NMDARs containing the GluN2A subunit and that it plays a crucial function in the synaptic stabilization of these receptors. Considering that protein-protein interactions govern the synaptic retention of NMDARs, the purpose of this work was to analyse the role of Rph3A and Rph3A/NMDAR complex in PD and LIDs, and to modulate Rph3A/GluN2A interaction to counteract the aberrant motor behaviour associated to chronic L-DOPA administration. Thus, an array of biochemical, immunohistochemical and pharmacological tools together with electron microscopy were applied in this study. Here we found that Rph3A is localized at the striatal postsynaptic density where it interacts with GluN2A. Notably, Rph3A expression at the synapse and its interaction with GluN2A-containing NMDARs were increased in parkinsonian rats displaying a dyskinetic profile. Acute treatment of dyskinetic animals with a cell-permeable peptide able to interfere with Rph3A/GluN2A binding significantly reduced their abnormal motor behaviour. Altogether, our findings indicate that Rph3A activity is linked to the aberrant synaptic localization of GluN2A-expressing NMDARs characterizing LIDs. Thus, we suggest that Rph3A/GluN2A complex could represent an innovative therapeutic target for those pathological conditions where NMDAR composition is significantly altered.

Keywords: Cell-permeable peptides; Levodopa-induced dyskinesias; N-methyl-d-aspartate receptor; Pharmacological target.

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aged
  • Aged, 80 and over
  • Animals
  • Antiparkinson Agents / therapeutic use
  • Antiparkinson Agents / toxicity
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Dyskinesia, Drug-Induced / drug therapy
  • Dyskinesia, Drug-Induced / metabolism*
  • Dyskinesia, Drug-Induced / pathology
  • Female
  • Humans
  • Levodopa / therapeutic use
  • Levodopa / toxicity*
  • Macaca mulatta
  • Male
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism*
  • Oxidopamine
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / pathology
  • Post-Synaptic Density / drug effects
  • Post-Synaptic Density / metabolism*
  • Post-Synaptic Density / pathology
  • Protein Binding / drug effects
  • Rabphilin-3A
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / drug effects
  • Synapses / metabolism
  • Tissue Culture Techniques
  • Vesicular Transport Proteins / antagonists & inhibitors
  • Vesicular Transport Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Antiparkinson Agents
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Vesicular Transport Proteins
  • Levodopa
  • Oxidopamine
  • N-methyl D-aspartate receptor subtype 2A