Crosstalk between receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCR) in the brain: Focus on heteroreceptor complexes and related functional neurotrophic effects

Neuropharmacology. 2019 Jul 1;152:67-77. doi: 10.1016/j.neuropharm.2018.11.018. Epub 2018 Nov 13.


Neuronal events are regulated by the integration of several complex signaling networks in which G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) are considered key players of an intense bidirectional cross-communication in the cell, generating signaling mechanisms that, at the same time, connect and diversify the traditional signal transduction pathways activated by the single receptor. For this receptor-receptor crosstalk, the two classes of receptors form heteroreceptor complexes resulting in RTKs transactivation and in growth-promoting signals. In this review, we describe heteroreceptor complexes between GPCR and RTKs in the central nervous system (CNS) and their functional effects in controlling a variety of neuronal effects, ranging from development, proliferation, differentiation and migration, to survival, repair, synaptic transmission and plasticity. In this interaction, RTKs can also recruit components of the G protein signaling cascade, creating a bidirectional intricate interplay that provides complex control over multiple cellular events. These heteroreceptor complexes, by the integration of different signals, have recently attracted a growing interest as novel molecular target for depressive disorders. This article is part of the Special Issue entitled 'Receptor heteromers and their allosteric receptor-receptor interactions'.

Keywords: Brain; GPCR; Heteroreceptor complexes; RTK; Transactivation.

Publication types

  • Review

MeSH terms

  • Brain / metabolism
  • Receptor Cross-Talk / physiology*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / physiology
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 2 / physiology
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, G-Protein-Coupled / physiology*
  • Signal Transduction / physiology


  • Receptors, G-Protein-Coupled
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 2