Dopamine-dependent signaling cascades
Dopamine binding with its receptors activates a number of intracellular
signaling cascades that modulate synaptic plasticity and SPN
excitability. Activation of adenylyl cyclase signaling pathway in
response to dopamine is best studied. Thus, dopamine binding with D1R
coupled with Gs/olf proteins stimulates production of
cyclic AMP and subsequent activation of PKA (Hervé, 2011; Nishi et
al. , 2011). In turn, PKA-mediated phosphorylation promotes multiple
intracellular changes, such as activation of N-type
Ca2+ channels and membrane expression of glutamate
receptors, inhibition of protein phosphatases and up-regulation of
transcriptional factors, leading to increased excitability of SPN of the
direct pathway (Missale et al. , 1998; Nishi et al. , 2011).
In opposite, dopamine binding with D2R coupled with Gi/0proteins suppresses cyclic AMP production and PKA activation in SPNs
(Missale et al. , 1998).
Results of the present study indicated that 3-day HU led to a decrease
in PKA activity in the dorsal striatum. According to the literature
data, these changes could result either from down-regulation of
D1R-linked signaling processes or from up-regulation of D2R-dependent
pathways. The roles of these cascades in observed dysregulation of PKA
claims further investigation. Nevertheless, our present data let us to
suppose that increased expression of D1R, as well as increased
pTH(Ser31), failed to compensate decreased dopamine innervation.
Moreover, down-regulation of PKA in the dorsal striatum of HU mice was
accompanied with decreased activity of CREB. This transcription factor
is involved in the regulation of long-term synaptic plasticity and
procedural memory and presents an important target of various
dopamine-induced signaling pathways associated with both D1R and D2R
(Pittenger et al. , 2006; Fasano et al. , 2009). Upon
dopamine stimulation of D1R CREB is mainly activated with participation
of PKA (Nishi et al. , 2011), while D2R stimulation can induce
CREB phosphorylation through PKC and CAMKII (Yan et al. , 1999).
ERK1/2 and Akt can mediate CREB activation downstream of both receptor
types (Brami-Cherrier et al. , 2002). However, our data did not
reveal any pronounced alterations in the activity of ERK1/2, CAMKII,
Akt, and GSK3β in the striatum of all studied groups. Thus, obtained
data demonstrated that in HU mice observed downregulation of TH activity
and subsequent decrease in dopamine production contributed mainly to the
inhibition of PKA-dependent signaling and its target - CREB.