Activation of Phosphatidylinositol-Linked D1-Like Receptor Modulates FGF-2 Expression in Astrocytes via IP3-Dependent Ca2+ Signaling

Zhang, Xinhua; Zhou, Zheng; Wang, Dakui; Li, Aiqun; Yin, Yanqing; Gu, Xiaosong; Ding, Fei; Zhen, Xuechu; Zhou, Jiawei

doi:10.1523/jneurosci.0389-09.2009

Cited by 49 publications

(46 citation statements)

References 31 publications

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“…This has led to the hypothesis that the behavioral actions of SKF-83959 may be mediated by its unique actions at PLC/calcium signaling at D 1 -D 2 heterodimers (Rashid et al , 2007a; Hasbi et al , 2009; Downes and Waddington, 1993; Deveney and Waddington, 1995; Fujita et al , 2010; Perreault et al , 2010; Arnt et al , 1992). This widespread belief that SKF-83959 is the first highly biased D 1 ligand has led many to consider it an important probe for studying the mechanisms related to D 1 signaling (Zhang et al , 2009; Yu et al , 2008; Zhang et al , 2007; Zhang et al , 2005; Perreault et al , 2011). …”

Section: Introductionmentioning

confidence: 99%

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

et al. 2014

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SKF-83959 [6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine] is reported to be a functionally selective dopamine D1 receptor ligand with high bias for D1-mediated phospholipase C (PLC) versus D1-coupled adenylate cyclase signaling. This signaling bias is proposed to explain behavioral activity in both rat and primate Parkinson’s disease models, and a D1-D2 heterodimer has been proposed as the underlying mechanism. We have conducted an in-depth pharmacological characterization of this compound in dopamine D1 and D2 receptors in both rat brain and heterologous systems expressing human D1 or D2 receptors. Contrary to common assumptions, SKF-83959 is similar to the classical, well-characterized partial agonist SKF38393 in all systems. It is a partial agonist (not an antagonist) at adenylate cyclase in vitro and ex vivo, and is a partial agonist in D1-mediated β-arrestin recruitment. Contrary to earlier reports, it does not have D1-mediated effects on PLC signaling in heterologous systems. Because drug metabolites can also contribute, its 3-N-demethylated analog also was synthesized and tested. As expected from the known structure-activity relationships of the benzazepines, this compound also had high affinity for the D1 receptor and somewhat higher intrinsic activity than the parent ligand, and also might contribute to in vivo effects of SKF-83959. Together, these data demonstrate that SKF-83959 is not a highly-biased functionally selective D1 ligand, and that its reported behavioral data can be explained solely by its partial D1 agonism in canonical signaling pathway(s). Mechanisms that have been proposed based on the purported signaling novelty of SKF-83959 at PLC should be reconsidered.

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Section: Introductionmentioning

confidence: 99%

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

et al. 2014

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“…In addition, the reports of PLC activation in either kidney or brain (Felder et al, 1989a,b;Dyck, 1990;Mahan et al, 1990;Undie and Friedman, 1990Vyas et al, 1992;Pacheco and Jope, 1997;Lee et al, 2004;Banday and Lokhandwala, 2007;Liu et al, 2009a;Zhang et al, 2009;Mizuno et al, 2012) show no effect at concentrations that would essentially saturate both D 1 and D 2 receptors (e.g., 10 mM). The rare reports showing functional Ca 21 effects at more reasonable concentrations also have anomalies.…”

Section: Hypothesis: D 1 -D 2 Heterodimer-mediated Activation Of Ga Qmentioning

confidence: 96%

“…Strikingly, in all prior publications reporting direct D 1 stimulation of PLC activity, the concentrations of SKF-83959 or other benzazepines required to elicit these effects were in the high micromolar/low millimolar range (Felder et al, 1989a,b;Dyck, 1990;Mahan et al, 1990;Undie and Friedman, 1990Vyas et al, 1992;Pacheco and Jope, 1997;Lee et al, 2004;Banday and Lokhandwala, 2007;Liu et al, 2009a;Zhang et al, 2009;Mizuno et al, 2012). No rationale was offered for use of SKF-83959 and chemically related benzazepines at concentrations far greater than their nanomolar K D values.…”

Section: Hypothesis: Skf-83959 Has No Intrinsic Activity At D 1 -Medimentioning

confidence: 99%

“…Because neither D 1 -binding sites nor D 1 mRNA are found in the cerebellum, this suggests an offtarget, rather than D 1 , mechanism. Finally, in almost every study using pharmacological antagonism of D 1 -PLC effects, the sole antagonist employed was the structurally similar benzazepine SCH23390 (Felder et al, 1989a,b;Dyck, 1990;Mahan et al, 1990;Undie and Friedman, 1990Vyas et al, 1992;Pacheco and Jope, 1997;Lee et al, 2004;Banday and Lokhandwala, 2007;Liu et al, 2009a;Zhang et al, 2009;Mizuno et al, 2012). Yet when structurally diverse antagonists were used, a very different picture emerges.…”

Section: Hypothesis: Skf-83959 Has No Intrinsic Activity At D 1 -Medimentioning

confidence: 99%

“…This would mean that SKF-83959 is the first highly biased, functionally selective D 1 ligand (Arnt et al, 1992;Undie and Friedman, 1992;Gnanalingham et al, 1995b) and would make it an important probe for studying mechanisms related to D 1 signaling (Zhang et al, 2005(Zhang et al, , 2007(Zhang et al, , 2009Yu et al, 2008;Liu et al, 2009a,b;Perreault et al, 2011Perreault et al, , 2014 (Perreault et al, 2014); SKF-83959 is "a selective [phosphatidylinositol]-linked D 1 -like receptor agonist" (Zhang et al, 2009); and there are "potential stimulant-antagonist actions, as observed with SKF-83959" (Neumeyer et al, 2003).…”

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confidence: 99%

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Dopamine D₁Receptor Signaling: Does Gα_Q–Phospholipase C Actually Play a Role?

Lee

Yang

Mailman

2014

J Pharmacol Exp Ther

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Despite numerous studies showing therapeutic potential, no central dopamine D 1 receptor ligand has ever been approved, because of potential limitations, such as hypotension, seizures, and tolerance. Functional selectivity has been widely recognized as providing a potential mechanism to develop novel therapeutics from existing targets, and a highly biased, functionally selective D 1 ligand might overcome some of the past limitations.

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Light‐controlled astrocytes promote human mesenchymal stem cells toward neuronal differentiation and improve the neurological deficit in stroke rats

Yang

Wan

et al. 2013

Glia

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Astrocytes are key components of the central nervous system (CNS) and release factors to support neural stem cell proliferation, differentiation, and migration. Adenosine 5'-triphosphate (ATP) is one of the key factors released upon activation of astrocytes that regulates the neural stem cell's function. However, it is not clear whether ATP derived from the depolarized astrocytes plays a vital role in promoting the neuronal differentiation of mesenchymal stem cells (MSCs) in vitro and in vivo. Herein, for the first time, we co-cultured MSCs with light-stimulated-channelrhodopsin-2 (ChR2)-astrocytes, and observed that the neuronal differentiation of MSCs was enhanced by expressing more neuronal markers, Tuj1 and NeuN. The ChR2-astrocyte-conditioned medium also stimulated MSCs differentiating into neuronal lineage cells by expressing more Tuj1 and Pax6, which was blocked by the P2X receptor antagonist, TNP-ATP. Then we found that light-depolarization of astrocytes significantly increased ATP accumulation in their bathing medium without impairing the cell membrane. We further found that ATP up-regulated the Tuj1, Pax6, FZD8 and β-catenin mRNA levels of MSCs, which could be reversed by application of TNP-ATP. Together these in vitro data provided convergent evidence that ATP from light-depolarized-astrocytes activated the wnt/β-catenin signaling of MSCs through binding to the P2X receptors, and promoted the neuronal differentiation of MSCs. Finally but importantly, our study also demonstrated in stroke rats that light-controlled astrocytes stimulated endogenous ATP release into the ischemic area to influence the transplanted MSCs, resulting in promoting the MSCs towards neuronal differentiation and improvements of neurological deficit.

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Activation of Phosphatidylinositol-Linked D1-Like Receptor Modulates FGF-2 Expression in Astrocytes via IP3-Dependent Ca2+ Signaling

Abstract: Fibroblast growth factor-2 (FGF-2

Cited by 49 publications

References 31 publications

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

Dopamine D₁Receptor Signaling: Does Gα_Q–Phospholipase C Actually Play a Role?

Light‐controlled astrocytes promote human mesenchymal stem cells toward neuronal differentiation and improve the neurological deficit in stroke rats

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Activation of Phosphatidylinositol-Linked D1-Like Receptor Modulates FGF-2 Expression in Astrocytes via IP3-Dependent Ca2+ Signaling

Abstract: Fibroblast growth factor-2 (FGF-2

Cited by 49 publications

References 31 publications

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

Dopamine D1Receptor Signaling: Does GαQ–Phospholipase C Actually Play a Role?

Light‐controlled astrocytes promote human mesenchymal stem cells toward neuronal differentiation and improve the neurological deficit in stroke rats

Contact Info

Product

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Dopamine D₁Receptor Signaling: Does Gα_Q–Phospholipase C Actually Play a Role?