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Receptor tyrosine kinase transactivation: fine-tuning synaptic transmission

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Abstract

G-protein-coupled receptors generate signals that promote gene transcription through the ‘transactivation’ of receptor tyrosine kinases (RTKs) and activation of the mitogen-activated protein kinase (MAPK) cascade – a process that involves RTK autophosphorylation and endocytosis. Pioneering work now suggests that D4-dopamine-receptor-mediated transactivation of the platelet-derived growth factor β receptor has immediate effects on synaptic neurotransmission via Ca2+-dependent inactivation of NMDA receptors. The demonstration of a physiological role for RTK transactivation in the CNS provides novel opportunities for understanding how aberrant dopamine signalling might contribute to cognitive and attention deficits associated with schizophrenia and attention-deficit hyperactivity disorder.

Section snippets

Focal adhesion complexes and synaptic transmission

One mechanism by which GPCRs modulate NMDA receptor signalling is via focal adhesion complexes. Focal adhesions are points of contact between cells and the extracellular matrix that can be utilized as scaffolds for the assembly of protein complexes required for GPCR-dependent activation of the Ras–mitogen-activated-protein kinase (MAPK) signalling cascade [10]. GPCR activation in fibroblasts leads to the rapid tyrosine phosphorylation and activation of p125 focal adhesion kinase (FAK), a

RTK transactivation and GPCR signaling

GPCRs and RTKs regulate many of the same signals and molecular intermediates involved in the MAPK signalling cascade and this convergence involves the transactivation of RTKs by GPCRs 3, 7, 8, 9. It is now appreciated that the receptors for epidermal growth factor (EGF), platelet-derived growth factor (PDGF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) can be transactivated in response to GPCR activation 3, 9, 15, 16. The transactivation of RTKs by GPCRs appears to

RTK transactivation and synaptic transmission

RTK transactivation by GPCRs leading to the activation of MAPK signalling is thought to regulate cell proliferation and differentiation, rather than short-term regulatory events [3]. This is what is unique and exciting about the recent study published in the journal Neuron by Kotecha and co-workers [32]. In their study, Kotecha et al. [32] demonstrate that D4 dopamine receptor transactivation of the PDGFβ receptor depresses excitatory neurotransmission mediated by the NMDA subtype of glutamate

Acknowledgements

I am the recipient of a Heart and Stroke Foundation of Canada MacDonald Scholarship, Premier's Research Excellence Award and Canada Research Chair in Molecular Neuroscience. This work was supported by CIHR grant MA-15506.

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