Publications by authors named "Daisy L Spark"

2 Publications

  • Page 1 of 1

β-Arrestin-2-Dependent Mechanism of GPR52 Signaling in Frontal Cortical Neurons.

ACS Chem Neurosci 2020 07 7;11(14):2077-2084. Epub 2020 Jul 7.

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

The orphan Gαs-coupled receptor GPR52 is expressed exclusively in the brain, predominantly in circuitry relating to symptoms of neuropsychiatric and cognitive disorders such as schizophrenia. While GPR52 agonists have displayed antipsychotic and procognitive efficacy in murine models, there remains limited evidence delineating the molecular mechanisms of these effects. Indeed, previous studies have solely reported canonical cAMP signaling and CREB phosphorylation downstream of GPR52 activation. In the present study, we demonstrated that the synthetic GPR52 agonist, 3-BTBZ, equipotently induces cAMP accumulation, ERK1/2 phosphorylation, and β-arrestin-1 and -2 recruitment in transfected HEK293T cells. In cultured frontal cortical neurons, however, 3-BTBZ-induced ERK1/2 phosphorylation was significantly more potent than cAMP signaling, with a more prolonged signaling profile than that in HEK293T cells. Furthermore, knock down of β-arrestin-2 in frontal cortical neurons abolished 3-BTBZ-induced ERK1/2 phosphorylation, but not cAMP accumulation. These results suggest a β-arrestin-2-dependent mechanism for GPR52-mediated ERK1/2 signaling, which may link to cognitive function . Finally, these findings highlight the context-dependence of GPCR signaling in recombinant cells and neurons, offering new insights into translationally relevant GPR52 signaling mechanisms.
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http://dx.doi.org/10.1021/acschemneuro.0c00199DOI Listing
July 2020

In the Loop: Extrastriatal Regulation of Spiny Projection Neurons by GPR52.

ACS Chem Neurosci 2020 07 7;11(14):2066-2076. Epub 2020 Jul 7.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia.

GPR52 is a Gα-coupled orphan receptor identified as a putative target for the treatment of schizophrenia. The unique expression and signaling profile of GPR52 in key areas of dopamine and glutamate dysregulation suggests its activation may resolve both cortical and striatal dysfunction in the disorder. GPR52 mRNA is enriched in the striatum, almost exclusively on dopamine D-expressing medium spiny neurons (MSNs), and to a lesser extent in the cortex, predominantly on D-expressing pyramidal neurons. Synthetic, small molecule GPR52 agonists are effective in preclinical models of psychosis; however, the relative contribution of cortical and striatal GPR52 is unknown. Here we show that the GPR52 agonist, 3-BTBZ, inhibits phencyclidine-induced hyperlocomotor activity to a greater degree than amphetamine-induced motor effects, suggesting a mechanism beyond functional antagonism of striatal dopamine D receptor signaling. Using DARPP-32 phosphorylation and electrophysiological recordings in either striatopallidal or striatonigral MSNs, we were surprised to find no significant effect of 3-BTBZ in striatopallidal MSNs, but GPR52-mediated effects in striatonigral MSNs, where its mRNA is absent. 3-BTBZ increases phosphorylation of T75 on DARPP-32 in striatonigral MSNs, an effect that was dependent on cortical inputs. A similar role for GPR52 in regulating extrastriatal glutamatergic drive onto striatonigral MSNs was also evident in recordings of spontaneous excitatory postsynaptic currents and was shown to be dependent on the metabotropic glutamate (mGlu) receptor subtype 1. Our results demonstrate that GPR52-mediated regulation of striatal function depends heavily on extrastriatal inputs, which may further support its utility as a novel target for the treatment of schizophrenia.
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http://dx.doi.org/10.1021/acschemneuro.0c00197DOI Listing
July 2020
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