Dopamine Receptor-mediated Ca2+ Signaling in Striatal Medium Spiny Neurons

Abstract

Inositol 1,4,5-trisphosphate (InsP 3 ) and cAMP are the two second messengers that play an important role in neuronal signaling. Here, we investigated the interactions of InsP 3 -and cAMP-mediated signaling pathways activated by dopamine in striatal medium spiny neurons (MSN). We found that in ϳ40% of the MSN, application of dopamine elicited robust repetitive Ca 2؉ transients (oscillations). In pharmacological experiments with specific agonists and antagonists, we found that the observed Ca 2؉ oscillations were triggered by activation of D1 class dopamine receptors (DARs). We further demonstrated that activation of phospholipase C was required for induction of dopamine- Dopamine is an important transmitter and neuromodulator in the brain. The cellular mechanisms by which dopamine affects neuronal function are only beginning to be elucidated (1, 2). Striatal medium spiny neurons (MSN) 1 express multiple subtypes of dopamine receptors (DARs) (3-5). On the basis of their molecular structure and pharmacological properties, DARs are divided into the D1 class (D1R and D5R) and D2 class (D2R, D3R, and D4R) (6). D1 class DARs are coupled to G s/olf , activation of adenylyl cyclase, and cAMP production (3). Activation of D2 class DARs has dual effects of inhibiting cAMP production (3) and activating phospholipase C␤ (PLC␤) (7). A putative D1 class DAR subtype coupled to PLC activation and phosphatidylinositol 4,5-diphosphate hydrolysis, but not to cAMP production, has been postulated (8 -10), but has not yet been isolated or cloned. Recently, a specific agonist for this receptor (SKF83959) was identified (11). The D1R-binding protein calcyon has been isolated by yeast two-hybrid methods (12). Association of D1/D5 receptors with calcyon enables coupling of D1/D5 receptors with G q/11 , resulting in PLC activation and inositol 1,4,5-trisphosphate (InsP 3 ) generation (12, 13). Cross-talk between cAMP and Ca 2ϩ signaling pathways plays an important role in dopaminergic signaling in the neostriatum (1). Activation of D1 class DARs enhances L-type Ca 2ϩ channel activity (14 -16) and currents via the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (17) and the N-methyl-D-aspartic acid (NMDA) receptor (18,19). In contrast, activation of D2 class DARs reduces L-type Ca 2ϩ currents (7) and NMDA receptor activity (20). D1/D5 receptormediated facilitation of L-type Ca 2ϩ channels and AMPA and NMDA receptors results from increased phosphorylation of these channels by protein kinase A (PKA) (16, 21) and decreased dephosphorylation of these channels by protein phosphatase-1 (PP1) (17,22,23). DARPP-32 (dopamine-and cAMPregulated phosphoprotein of M r 32,000) (24, 25) is partly responsible for inhibition of PP1 activity following activation of D1/D5 receptors (26). DARPP-32 phosphorylated by PKA at a single threonine residue (Thr-34) is transformed into a potent inhibitor of PP1, which in turn regulates the phosphorylation state of many neurotransmitter receptors and voltage-gated ion channels (1).The type 1 inos...

Dopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease

“…From these results, we concluded that dopamine potentiates glutamate-induced Ca 2ϩ signals in cultured WT and YAC128 MSNs via D 1 -class dopamine receptors. This conclusion is in agreement with our previous findings that the D 1 -class dopamine receptors, but not D 2 -class dopamine receptors, can greatly potentiate Ca 2ϩ responses in cultured rat MSNs (Tang and Bezprozvanny, 2004). Additional analysis revealed that the glutamate-induced Ca 2ϩ levels reached in the presence of 25 M SKF38393 were significantly ( p Ͻ 0.01) higher in YAC128 MSNs than in WT MSNs, consistent with potentiating effects of mutant Htt-128Q on intracellular Ca 2ϩ signals in striatal MSNs (Tang et al, 2005).…”

“…D 1 -class DARs are coupled to G s/olf , activation of adenyl cyclase, and cAMP production (Missale et al, 1998). PKA potentiates glutamate-induced Ca 2ϩ signals by facilitating activity of NMDAR (Levine et al, 1996;Flores-Hernandez et al, 2002) and InsP 3 R1 (Tang et al, 2003a;Tang and Bezprozvanny, 2004). In HD MSNs, NR2B-and InsP 3 R1-mediated Ca 2ϩ signaling is further facilitated by Htt exp (Zeron et al, 2002(Zeron et al, , 2004Tang et al, 2003bTang et al, , 2005.…”

“…D 1 -class DARs are coupled to G s/olf , activation of adenyl cyclase, and cAMP production (Missale et al, 1998). PKA activation modulates the glutamate-related Ca 2ϩ signaling pathway by facilitating the activity of NMDAR (Levine et al, 1996;FloresHernandez et al, 2002), AMPA receptor (Yan et al, 1999), and InsP 3 R1 (Tang et al, 2003a;Tang and Bezprozvanny, 2004). As a result of the convergence of cAMP/PKA and NMDAR/InsP 3 R1-mediated signaling pathways on Ca 2ϩ (Fig.…”

Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development

“…Although signaling via the adenylyl cyclase-cAMP system is the principal mode of action, dopamine receptors also activate phospho-lipase C via the Gq/ 11 system and increase intracellular calcium levels [16,39]. Dopamine receptors also interact with glutamate receptors [4,21,44] and mobilize intracellular Ca 2+ stores [23,51].…”

Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival

“…Moreover, Tang and colleagues (22) discovered a direct association between PP1 and InsP 3 R-1 and established that the association with PP1 facilitates dephosphorylation of PKA-phosphorylated InsP 3 R-1. These investigators established the role of AKAP9, a multifunctional PKA anchoring protein, in docking PKA and PP1 to InsP 3 R-1 (28) and in experiments with medium spiny neurons from DARPP-32 knock-out mice, demonstrated a regulatory role of DARPP-32 in dopamine-induced Ca 2+ oscillations (29). Although these results advance our understanding of crosstalk between cAMP and InsP 3 -mediated Ca 2+ signaling pathways in the brain, much less is known about the role of DARPP-32 in peripheral tissues, including lymphocytes, although DARPP-32 has been shown to increase the phosphorylation and activity of various ion channels (30).…”