Role of GABA_B receptors in dopamine/DARPP-32 signaling

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Dopamine plays a central role in the regulation of psychomotor function in the brain. Many of the actions of dopamine are mediated through signal transduction pathways that involve DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa). When DARPP-32 is phosphorylated on Thr34, it is converted into a potent inhibitor of protein phosphatase-1(PP-1), and thereby controls the phosphorylation state and activity of many downstream physiological effectors. Since actions of neurotransmitters in neostriatal neurons are integrated to DARPP-32 phosphorylation, DARPP-32 is suitable for the analysis of the convergence of intracellular signal. In this study, we investigated the role of GABAB receptors in the dopamine/DARPP-32 signaling cascade using mouse neostriatal slices.Activation of GABA_B receptors with its agonist, baclofen (200 μM), resulted in the stimulation of Thr34 (PKA-site) and Ser97 (CK2-site) phosphorylation, but did not affect Thr75(Cdk5-site)or Ser130 (CK2-site) phosphorylation. Since neurotensin stimulates the release of dopamine and activates dopamine D1 receptor/PKA/DARPP-32 Thr34 signaling, the role of GABA_B receptors in neurotensin-mediated DARPP-32 phosphorylation was examined. Interestingly, both a GABA_B receptor agonist, baclofen(200 μM), and a GABA_B receptor antagonist, hydroxysaclofen (100μM), potentiated neurotensin-mediated DARPP-32 Thr34 phosphorylation. These results demonstrate that GABA_B receptors have both stimulatory and inhibitory effects on dopamine signaling in the striatum by acting at multiple sites in pre- and post-synaptic neurons. We are conducting further studies to clarify the GABA_B receptor signaling cascades.