Moonlighting proteins and protein-protein interactions as neurotherapeutic targets in the G protein-coupled receptor field

Neuropsychopharmacology. 2014 Jan;39(1):131-55. doi: 10.1038/npp.2013.242. Epub 2013 Sep 6.


There is serious interest in understanding the dynamics of the receptor-receptor and receptor-protein interactions in space and time and their integration in GPCR heteroreceptor complexes of the CNS. Moonlighting proteins are special multifunctional proteins because they perform multiple autonomous, often unrelated, functions without partitioning into different protein domains. Moonlighting through receptor oligomerization can be operationally defined as an allosteric receptor-receptor interaction, which leads to novel functions of at least one receptor protomer. GPCR-mediated signaling is a more complicated process than previously described as every GPCR and GPCR heteroreceptor complex requires a set of G protein interacting proteins, which interacts with the receptor in an orchestrated spatio-temporal fashion. GPCR heteroreceptor complexes with allosteric receptor-receptor interactions operating through the receptor interface have become major integrative centers at the molecular level and their receptor protomers act as moonlighting proteins. The GPCR heteroreceptor complexes in the CNS have become exciting new targets for neurotherapeutics in Parkinson's disease, schizophrenia, drug addiction, and anxiety and depression opening a new field in neuropsychopharmacology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Antiparkinson Agents / pharmacology
  • Antiparkinson Agents / therapeutic use
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use
  • Cocaine / adverse effects
  • Cocaine / pharmacology
  • Cocaine-Related Disorders / drug therapy
  • Cocaine-Related Disorders / metabolism
  • Depression / drug therapy
  • Depression / metabolism
  • Drug Discovery / methods*
  • Humans
  • Molecular Targeted Therapy / methods*
  • Parkinson Disease / drug therapy
  • Parkinson Disease / metabolism
  • Protein Interaction Mapping / methods*
  • Receptors, G-Protein-Coupled / metabolism*
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism


  • Antidepressive Agents
  • Antiparkinson Agents
  • Antipsychotic Agents
  • Receptors, G-Protein-Coupled
  • Cocaine