Signaling pathway involved in the pro-apoptotic effect of dopamine in the GH3 pituitary cell line

Arnaud Jaubert, François Ichas, Laurence Bresson-Bepoldin
Neuroendocrinology. 2006-01-01; 83(2): 77-88
DOI: 10.1159/000094044

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Besides its physiological role as a neurotransmitter, dopamine (DA) induces
apoptosis in the central nervous system. This effect is mediated partly by the DA
transporter (DAT) and involves reactive oxygen species (ROS) formation as well as
oxidative stress. In the pituitary, the inhibitory control by DA of prolactin
release and synthesis and lactotrope cell proliferation is well known, while the
pro-apoptotic effect of DA remains unclear. Our aim was to study the
pro-apoptotic effect of DA in the GH3 mammosomatotrope cell line and determine
the DA mechanism that leads to apoptosis in these cells. Using flow cytometry,
Western blot, and confocal microscopy, we showed for the first time that DA
induced: (1) loss of mitochondrial potential; (2) relocation of Bax to the
mitochondria; (3) cytochrome c release; (4) caspase-3 activation, and (5) nuclear
fragmentation, resulting in apoptosis. We observed that DAT was expressed in GH3
cells and participated in the DA effect, as apoptosis was significantly reversed
in the presence of DAT inhibitors. Direct measurement showed that DA rapidly
increased the formation of intracellular ROS. The antioxidant N-acetyl-L-cysteine
(NAC) effectively blocked DA-induced ROS formation and apoptosis. Neither JNK nor
p38 were involved in this process, so we suggest that the mitochondrial pore of
transition is the likely target of the ROS generated by DA. These data provide
the first evidence that DA triggers apoptosis in pituitary cells via a mechanism
involving DAT and oxidative stress. These findings may be particularly relevant
in understanding lactotrope apoptosis during postnatal life.


Auteurs Bordeaux Neurocampus