Ligands for ErbB1-4 receptor tyrosine kinases, such as epidermal growth factor (EGF) and neuregulins, regulate brain development and function. Thus, abnormalities in their signaling are implicated in the etiology or pathology of schizophrenia and Parkinson's disease. Among the ErbB receptors, ErbB1, and ErbB4 are expressed in dopamine and GABA neurons, while ErbB1, 2, and/or 3 are mainly present in oligodendrocytes, astrocytes, and their precursors. Thus, deficits in ErbB signaling might contribute to the neurological and psychiatric diseases stemming from these cell types. By incorporating the latest cancer molecular biology as well as our recent progress, we discuss signal cross talk between the ErbB1-4 subunits and their neurobiological functions in each cell type. The potential contribution of virus-derived cytokines (virokines) that mimic EGF and neuregulin-1 in brain diseases are also discussed.

Epidermal growth factor (EGF) is a member of a structurally related family containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFa) that exerts neurotrophic activity on midbrain dopaminergic neurons. To examine neurotrophic abnormality in Parkinson's disease (PD), we measured the protein content of EGF, TGFa, and HB-EGF in post-mortem brains of patients with Parkinson's disease and age-matched control subjects. Protein levels of EGF and tyrosine hydroxylase were decreased in the prefrontal cortex and the striatum of patients. In contrast, HB-EGF and TGFa levels were not significantly altered in either region. The expression of EGF receptors (ErbB1 and ErbB2, but not ErbB3 or ErbB4) was down-regulated significantly in the same forebrain regions. The same phenomenon was mimicked in rats by dopaminergic lesions induced by nigral 6-hydroxydopamine infusion. EGF and ErbB1 levels in the striatum of the PD model were markedly reduced on the lesioned side, compared with the control hemisphere. Subchronic supplement of EGF in the striatum of the PD model locally prevented the dopaminergic neurodegeration as measured by tyrosine hydroxylase immunoreactivity. These findings suggest that the neurotrophic activity of EGF is maintained by afferent signals of midbrain dopaminergic neurons and is impaired in patients with Parkinson's disease. Parkinson's disease (PD) is a neurodegenerative disease, caused by progressive degeneration of nigrostriatal dopaminergic neurons. Genetic linkage studies have identified the genes responsible for familial types of PD and hint at the molecular mechanism of this illness (Mayeux 2003; Warner and Schapira 2003 for review). More than 95% cases of PD, however, are sporadic and the etiology is still poorly understood. Dopaminergic neurons in the substantia nigra (SN) appear to receive neurotrophic signals from their main target region of the striatum (Unsicker 1994;Olson 1997;Kholodilov et al. 2004). Surgical lesions of the nigrostriatal pathway result in degeneration of the dopaminergic neurons, but the administration of neurotrophic factors rescues them from cell death or enhances their regeneration (Ventrella 1993;Beck et al. 1995;Tseng et al. 1997;Volpe et al. 1998). What is the molecular nature of the trophic support for the SN dopaminergic neurons? In vitro culture studies indicate that a variety of neurotrophic substances support cell survival and growth of SN dopaminergic neurons. Such neurotrophic factors include brain-derived neurotrophic factor, fibroblast growth factors, IL-1, glial cell-derived neurotrophic factor, epidermal growth factor (EGF), heparinbinding EGF (HB-EGF), and transforming growth factor alpha (TGFa;Casper et al. 1991;Hyman et al.

Postsynaptic molecules with PDZ domains (PDZ proteins) interact with various glutamate receptors and regulate their subcellular trafficking and stability. In rat neocortical development, the protein expression of AMPA-type glutamate receptor GluR1 lagged behind its mRNA expression and rather paralleled an increase in PDZ protein levels. One of the neurotrophins, brain-derived neurotrophic factor (BDNF), appeared to contribute to this process, regulating the PDZ protein expression. In neocortical cultures, BDNF treatment upregulated SAP97, GRIP1, and Pick1 PDZ proteins. Conversely, BDNF gene targeting downregulated these same PDZ molecules. The BDNF-triggered increases in PDZ proteins resulted in the elevation of their total association with the AMPA receptors GluR1 and GluR2/3, which led to the increase in AMPA receptor proteins. When Sindbis viruses carrying GluR1 or GluR2 C-terminal decoys disrupted their interactions, GluR2 C-terminal decoys inhibited both BDNF-triggered GluR1 and GluR2/3 increases, whereas GluR1 C-terminal decoys blocked only the BDNF-triggered GluR1 increase. In agreement, coexpression of SAP97 and GluR1 in nonneuronal HEK293 cells increased both proteins compared with their single transfection, implying mutual stabilization. This work reveals a novel function of BDNF in postsynaptic development by regulating the PDZ protein expression.

In hippocampal neurons, the exocytotic process of ␣-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors is known to depend on activation of N-methyl-D-aspartate channels and its resultant Ca 2؉ influx from extracellular spaces. Here we found that brain-derived neurotrophic factor (BDNF) induced a rapid surface translocation of AMPA receptors in an activity-independent manner in developing neocortical neurons. The receptor translocation became evident within hours as monitored by

In addition to its role as a neurotransmitter, dopamine can stimulate neurite outgrowth and morphological effects upon primary neurons. To investigate the signal transduction mechanisms used by dopamine in developing striatal neurons, we focused upon the effects of activating the dopamine D1 receptor. Using the D1 receptor agonist SKF38393, we found that Trk neurotrophin receptors were activated in embryonic day 18 striatal neurons. K-252a, a Trk tyrosine kinase inhibitor, and a dopamine D1 receptor antagonist could block the effects of SKF38393. The increase in TrkB phosphorylation was not the result of increased neurotrophin production. Induction of TrkB activity by SKF38393 was accompanied by the phosphorylation of several Trk signaling proteins, including phospholipase C␥, Akt, and MAPK. Biotinylation experiments followed by immunostaining by phospho-TrkB-specific antibodies indicated that the mechanism involved increased TrkB surface expression by dopamine D1 receptor activation. This increase in cell surface TrkB expression was dependent upon an increase in intracellular Ca 2؉ . These results indicate that stimulation of dopamine D1 receptors can be coupled to the neurotrophin receptor signaling to mediate the effects of dopamine upon striatal neurons. Dopamine, the major neurotransmitter released from dopaminergic neurons, modulates neuronal activity (1-3) and influences key physiological functions related to locomotor activity, reward, and cognition (4,5). Dopamine also appears to exert several developmental roles. In the lateral ganglionic eminence, dopamine receptors modulate the cell cycle of progenitor cells (6). Dopamine regulates neuronal differentiation and maturation, such as neurite extension and development of growth cones (7-9). However, the molecular mechanisms for these developmental activities have not yet been defined. Dopamine receptors are classified as D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors (10). Activation of D1-like receptors enhances L-type calcium ion (Ca 2ϩ ) channel activity and increases intracellular Ca 2ϩ concentration (11-13). Dopamine receptors are G protein-coupled receptors (GPCRs) 3 that regulate the signaling results in cyclic 3Ј-5Ј AMP (cAMP) accumulation because of coupling with the heterotrimeric G protein subunits (14,15). A number of GPCRs can transactivate receptor tyrosine kinases. This suggests that dopamine receptors may regulate trophic effects more broadly by using transactivation of other receptors.Neurotrophins, such brain-derived neurotrophic factor (BDNF) and neurotrophin-3, are widely expressed in cortex, cerebellum, and hippocampus and have well established effects upon the differentiation and development of many neuronal populations in the central nervous system (16). In addition to neurotrophin binding to Trk receptors, it has been appreciated that Trk receptors can be transactivated by ligands that use GPCRs (17,18). Transactivation of Trk receptors has been shown to account for neuroprotection and neuronal migration (19,20).In th...