Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes

Rithwick Rajagopal, Zhe Yu Chen, Francis S. Lee, Moses V. Chao

Research output: Contribution to journalArticlepeer-review

207 Scopus citations

Abstract

Neurotrophins, such as NGF and BDNF, activate Trk receptor tyrosine kinases through receptor dimerization at the cell surface followed by autophosphorylation and intracellular signaling. It has been shown that activation of Trk receptor tyrosine kinases can also occur via a G-protein-coupled receptor (GPCR) mechanism, without involvement of neurotrophins. Two GPCR ligands, adenosine and pituitary adenylate cyclase-activating polypeptide (PACAP), can activate Trk receptor activity to increase the survival of neural cells through stimulation of Akt activity. To investigate the mechanism of Trk receptor transactivation, we have examined the localization of Trk receptors in PC12 cells and primary neurons after treatment with adenosine agonists and PACAP. In contrast to neurotrophin treatment, Trk receptors were sensitive to transcriptional and translational inhibitors, and they were found predominantly in intracellular locations particularly associated with Golgi membranes. Biotinylation and immunostaining experiments confirm that most of the transactivated Trk receptors are found in intracellular membranes. These results indicate that there are alternative modes of activating Trk receptor tyrosine kinases in the absence of neurotrophin binding at the cell surface and that receptor signaling may occur and persist inside of neuronal cells.

Original languageEnglish
Pages (from-to)6650-6658
Number of pages9
JournalJournal of Neuroscience
Volume24
Issue number30
DOIs
StatePublished - Jul 28 2004

Keywords

  • Adenosine
  • Basal forebrain
  • Golgi apparatus
  • NGF
  • PACAP
  • Tyrosine phosphorylation

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