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J. Neurosci. 24 (30): 6650-6658

Copyright © 2004 by the Society for Neuroscience.

Cellular/Molecular

Transactivation of Trk Neurotrophin Receptors by G-Protein-Coupled Receptor Ligands Occurs on Intracellular Membranes

Rithwick Rajagopal,1 Zhe-Yu Chen,2 Francis S. Lee,2 , and Moses V. Chao1

1Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Departments of Cell Biology and Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, and 2Department of Psychiatry, Weill Medical College of Cornell University, New York, New York 10021

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.

Key Words: NGF • tyrosine phosphorylation • basal forebrain • adenosine • PACAP • Golgi apparatus

Received for publication Jan 2, 2004. Revision received June 8, 2004. Accepted for publication June 14, 2004.

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