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.