Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra

Abstract

Glial cell line-derived neurotrophic factor (GDNF) improves motor dysfunction associated with aging in rats and non-human primates, in animal models of Parkinson's disease, and may improve motoric function in patients with advanced Parkinson's disease. These improvements are associated with increased dopamine function in the nigrostriatal system, but the molecular events associated with this increase are unknown. In these studies, 100 lg of GDNF was injected into the striatum of normal aged (24-month-old) male Fischer 344 rats. The protein levels and phosphorylation of TH, ERK1/2, and related proteins were determined by blot-immunolabeling of striatum and substantia nigra harvested 30 days after injection. In GDNF-treated rats, TH phosphorylation at Ser31 increased 40% in striatum and 250% in the substantia nigra. In the substantia nigra, there was a significant increase in ERK1 phosphorylation. In striatum, there was a significant increase in ERK2 phosphorylation. Microdialysis studies in striatum showed that both amphetamine-and potassiumevoked dopamine release in GDNF recipients were significantly increased. These data show that GDNF-induced increases in dopamine function are associated with a sustained increase in TH phosphorylation at Ser31, which is greatest in the substantia nigra and maintained for at least one month following a single striatal administration of GDNF. These findings, taken from the nigrostriatal system of normal aged rats, may help explain the long lasting effects of GDNF on dopamine function and prior studies supporting that a major effect of GDNF involves its effects on dopamine storage and somatodendritic release of dopamine in the substantia nigra.

mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

“…Using an in vitro model, GDNF stimulation of distal axons resulted in activation of downstream signaling of Erk1/2 and Akt phosphorylation in the axons, and RET and Akt phosphorylation in the cell bodies, demonstrating the retrograde propagation of an intracellular GDNF-mediated signal (Coulpier and Ibanez, 2004;Tomac et al, 1995b). A retrograde propagation of GDNF signaling is also supported by data showing Erk1/2 activation in the substantia nigra following striatal GDNF injection (Salvatore et al, 2004;Lindgren et al, 2008). In the present study, following LY379268 treatment Erk1/2 signaling pathway was found significantly activated also in the substantia nigra.…”

Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

“…A single GDNF administration increases K + -evoked DA overflow throughout the striatum and in primary cultures of dopaminergic neurons, without affecting the release of GABA or the basal levels of DA [38,238,288]. The enhancement of DA overflow is likely caused by increased DA synthesis as GDNF strongly increases TH phosphorylation [288]. In support of this view, amperometric recordings demonstrated a > 3 fold increase in the amount of DA released per exocytotic event in dopaminergic neurons [38].…”

“…Though GDNF rapidly and reversibly potentiates voltage-activated Ca 2+ currents as well as the amplitude and frequency of spontaneous and evoked excitatory autaptic currents in dopaminergic neurons [207], GDNF is particularly noted for its delayed (days-weeks), long-term (days-weeks) effects, which occur even after a single administration. A single GDNF administration increases K + -evoked DA overflow throughout the striatum and in primary cultures of dopaminergic neurons, without affecting the release of GABA or the basal levels of DA [38,238,288]. The enhancement of DA overflow is likely caused by increased DA synthesis as GDNF strongly increases TH phosphorylation [288].…”

Driving GDNF expression: The green and the red traffic lights

“…GDNF was shown to enhance dopamine biosynthesis due to phosphorylation and increased activity of TH (Kobori et al, 2004;Salvatore et al, 2004), and increased activation of the enzyme producing BH4 (5,6,7,8-tetrahydrobiopterin), a cofactor for TH (Bauer et al, 2002). This enhancement of dopamine synthesis likely leads to an increase in quantal release as observed in postnatal dopaminergic neurons in culture (Pothos et al, 1998).…”