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Logo of asnneuroAboutEditorial BoardInfo for AuthorsSubmissionASN NEUROASN NEURO
ASN Neuro. 2012; 4(6): e00098.
Published online 2012 September 24. Prepublished online 2012 August 21. doi:  10.1042/AN20120013
PMCID: PMC3449306

Dopamine D2 receptor-mediated Akt/PKB signalling: initiation by the D2S receptor and role in quinpirole-induced behavioural activation


The short and long isoforms of the dopamine D2 receptor (D2S and D2L respectively) are highly expressed in the striatum. Functional D2 receptors activate an intracellular signalling pathway that includes a cAMP-independent route involving Akt/GSK3 (glycogen synthase kinase 3). To investigate the Akt/GSK3 response to the seldom-studied D2S receptor, we established a rat D2S receptor-expressing cell line [HEK (human embryonic kidney)-293/rD2S]. We found that in HEK-293/rD2S cells, the D2/D3 agonists bromocriptine and quinpirole significantly induced Akt and GSK3 phosphorylation, as well as ERK1/2 (extracellular-signal-regulated kinase 1/2) activation. The D2S receptor-induced Akt signals were profoundly inhibited by the internalization blockers monodansyl cadaverine and concanavalin A. Activation of the D2S receptor in HEK-293/rD2S cells appeared to trigger Akt/phospho-Akt translocation to the cell membrane. In addition to our cell culture experiments, we studied D2 receptor-dependent Akt in vivo by systemic administration of the D2/D3 agonist quinpirole. The results show that quinpirole evoked Akt-Ser473 phosphorylation in the ventral striatum. Furthermore, intra-accumbens administration of wortmannin, a PI3K (phosphoinositide 3-kinase) inhibitor, significantly suppressed the quinpirole-evoked behavioural activation. Overall, we demonstrate that activation of the dopamine D2S receptor stimulates Akt/GSK3 signalling. In addition, in vivo Akt activity in the ventral striatum appears to play an important role in systemic D2/D3 agonist-induced behavioural activation.

Keywords: Akt (protein kinase B), dopamine D2S receptor, glycogen synthase kinase 3, nucleus accumbens, receptor internalization
Abbreviations: CNS, central nervous system; ConA, concanavalin A; CREB, cAMP-response-element-binding protein; Cy3, indocarbocyanine; DA, dopamine; DAPI, 4′,6-diamidino-2-phenylindole; EGF, epidermal growth factor; ERK, extracellular-signal-regulated kinase; GSK, glycogen synthase kinase; HEK, human embryonic kidney; HRP, horseradish peroxidase; MAPK, mitogen-activated protein kinase; MDC, monodansylcadaverine; MEK, MAPK/ERK kinase; MEM, minimum essential medium; METH, methamphetamine; Nrf2, nuclear factor-erythroid 2-related factor 2; PDGF, platelet-derived growth factor; PI3K, phosphoinositide 3-kinase

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