Role of adrenoceptors in the regulation of dopamine/DARPP‐32 signaling in neostriatal neurons

Abstract

J. Neurochem. (2010) 113, 1046–1059. Abstract Studies in animal models of Parkinson’s disease have revealed that degeneration of noradrenaline neurons is involved in the motor deficits. Several types of adrenoceptors are highly expressed in neostriatal neurons. However, the selective actions of these receptors on striatal signaling pathways have not been characterized. In this study, we investigated the role of adrenoceptors in the regulation of dopamine/dopamine‐ and cAMP‐regulated phosphoprotein of Mr 32 kDa (DARPP‐32) signaling by analyzing DARPP‐32 phosphorylation at Thr34 [protein kinase A (PKA)‐site] in mouse neostriatal slices. Activation of β1‐adrenoceptors induced a rapid and transient increase in DARPP‐32 phosphorylation. Activation of α2‐adrenoceptors also induced a rapid and transient increase in DARPP‐32 phosphorylation, which subsequently decreased below basal levels. In addition, activation of α2‐adrenoceptors attenuated, and blockade of α2‐adrenoceptors enhanced dopamine D1 and adenosine A2A receptor/DARPP‐32 signaling. Chemical lesioning of noradrenergic neurons mimicked the effects of α2‐adrenoceptor blockade. Under conditions of α2‐adrenoceptor blockade, the dopamine D2 receptor‐induced decrease in DARPP‐32 phosphorylation was attenuated. Our data demonstrate that β1‐ and α2‐adrenoceptors regulate DARPP‐32 phosphorylation in neostriatal neurons. Gi activation by α2‐adrenoceptors antagonizes Gs/PKA signaling mediated by D1 and A2A receptors in striatonigral and striatopallidal neurons, respectively, and thereby enhances D2 receptor/Gi signaling in striatopallidal neurons. α2‐Adrenoceptors may therefore be a therapeutic target for the treatment of Parkinson’s disease.

Immunohistochemical Localization of DARPP-32 in the Brain of Two Lungfishes: Further Assessment of Its Relationship with the Dopaminergic System

“…These mismatches have also been reported in the dorsal and central nuclei of ventral telencephalon of zebrafish [Robra and Thirumalai, 2016], in the lateroventral septum, cerebellum and reticular formation of amphibians , the septal region, the superficial part of the medial cortex, pretectum and rhombencephalic ventromedial tegmentum of reptiles [Smeets et al, 2001[Smeets et al, , 2003, and in the neocortex and cerebellum of mammals [Ouimet et al, 1984[Ouimet et al, , 1992. These data support that DARPP-32 may not only be regulated by dopamine, but also by glutamate, serotonin, noradrenalin, nitric oxide, or somatostatin Svenningsson et al, 2002;Andersson et al, 2005;Nishi et al, 2005;Hara et al, 2010;Rajput et al, 2012;Yuste et al, 2012].…”

“…In addition, DARPP-32 is phosphorylated/dephosphorylated by several other kinases and phosphatases with multiple cellular responses, including the regulation of cytonuclear trafficking and chromatin response [Johansen and Johansen, 2006;Stipanovich et al, 2008;Yger and Girault, 2011]. Therefore, DARPP-32 acts as a "third messenger" that integrates multiple signaling pathways important to the proper functioning of the neural circuits in which it is expressed Svenningsson et al, 2002;Andersson et al, 2005;Kuroiwa et al, 2008;Hara et al, 2010;Yger and Girault, 2011].…”

Immunohistochemical localization of DARPP-32 in the brain and spinal cord of anuran amphibians and its relation with the catecholaminergic system

“…the lateroventral septum and the cerebellum of Rana and the reticular formation of both species of anurans studied), reptiles (e.g. septal region, superficial part of the medial cortex, pretectum and rhombencephalic ventromedial tegmentum; Smeets et al, 2001Smeets et al, , 2003 and mammals (Ouimet et al, 1984(Ouimet et al, , 1992 supporting the notion that DARPP-32 may be regulated by factors other than dopamine like glutamate, serotonin, noradrenalin and cannabinoid receptors (Greengard et al, 1998;Svenningsson et al, 2002;Andersson et al, 2005;Nishi et al, 2005;Hara et al, 2010).…”

“…The stimulation of dopamine D 1 -receptor enhances the phosphorylation of DARPP-32 ) that acts as a potent protein phosphatase-1 inhibitor , whereas the activation of NMDA receptor promotes the elevation of intracellular calcium and induces dephosphorylation of DARPP-32 (Halpain et al, 1990) reducing its phosphatase-1 inhibitory activity. Therefore, DARPP-32 acts like a third messenger that integrates multiple signaling pathways in the brain (Greengard et al, 1998;Svenningsson et al, 2002;Andersson et al, 2005;Kuroiwa et al, 2008;Hara et al, 2010).…”

Behavioral and Cellular Modulation of l-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-Hydroxydopamine-Lesioned Rat

“…Ample evidence exists showing that ␤AR activity modulates DA release in the striatum, suggesting a presynaptic mechanism for (Ϯ)propranolol in LID (Reisine et al, 1982;Goshima et al, 1991). Recent research has suggested an additional postsynaptic mechanism; antagonism of ␤ 1 AR was shown to reduce downstream phosphorylation of dopamine-and cyclic-AMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 (Hara et al, 2010), which is clinically important because high levels of pThr 34 -DARPP-32 are implicated in the expression of LID (Santini et al, 2007;Bateup et al, 2010).…”