Physiological role of RTK transactivation in the central nervous system and neuropsychiatric diseases

G protein-coupled receptors (GPCRs) generate signals that promote gene transcription through the 'transactivation' of receptor tyrosine kinases (RTKs) such as the receptors for epidermal growth factor, fibroblast growth factor, platelet-derived growth factor (PDGF), and neurotrophins. RTKs and downstream signaling pathways activated in response to GPCR-mediated stimulation elicit phenotypic responses. Transactivation is essential for the specificity and fidelity of signal transduction and biological responses and is particularly important in the central nervous system (CNS), where RTKs mediate key events in the development and maintenance of neuronal circuits. Recent evidence indicates that RTK transactivation may be involved in the pathophysiology of neuropsychiatric diseases. Dopamine, a major transmitter and neuromodulator in the CNS, is implicated in psychiatric diseases. A GPCR, the D4 dopamine receptor, inhibits 1) excitatory transmission mediated by the N-methyl-D-aspartate (NMDA) glutamate receptor subtype and 2) synaptic transmission through transactivation of the PDGF receptor. The demonstration of a physiological role for RTK transactivation in the CNS provides opportunities for understanding how aberrant dopamine signaling might contribute to neuropsychiatric diseases and for producing novel treatment strategies for these diseases.