High-Content Single-Cell Förster Resonance Energy Transfer Imaging of Cultured Striatal Neurons Reveals Novel Cross-Talk in the Regulation of Nuclear Signaling by Protein Kinase A and Extracellular Signal-Regulated Kinase 1/2

Jones-Tabah, Jace; Martin, R. D.; Tanny, Jason C.; Clarke, Paul B. S.; Hébert, Terence E.

doi:10.1124/molpharm.121.000290

Cited by 10 publications

(15 citation statements)

References 51 publications

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“…As described previously, after activation of D1Rs in cortical and striatal neurons, PKA can translocate to (or become activated within) the nucleus, but to different extents and with different kinetics (Yapo et al, 2018 ; Jones-Tabah et al, 2021 ). Specifically, in cortical neurons, the activity of nuclear PKA increases slowly, and only upon sustained D1R stimulation.…”

Section: Signal Transduction Via the D1rmentioning

confidence: 78%

“…The temporal dynamics of nuclear PKA activation in these neurons is consistent with passive diffusion of the activated PKA catalytic subunit into the nuclear compartment. By contrast, in striatal neurons D1R stimulation produces a rapid, robust and sustained nuclear PKA signal that can be elicited even by a transient pulse of released dopamine (Yapo et al, 2018 ; Jones-Tabah et al, 2021 ). The rate of nuclear PKA activation in striatal neurons suggests an additional mechanism at play beyond passive subunit diffusion.…”

Section: Signal Transduction Via the D1rmentioning

confidence: 99%

“…ERK1/2 are proximally activated by phosphorylation mediated principally by MEK, but the D1R-associated signaling cascades that ultimately lead to ERK1/2 activation are numerous. Although D1R activation alone can stimulate ERK1/2 both in cultured striatal neurons (Jones-Tabah et al, 2021 ) and certain striatal areas in vivo (Gerfen et al, 2002 ), maximal ERK1/2 activation in the rodent striatum has been reported to require concurrent activation of both D1 and NMDA receptors (Valjent et al, 2005 ). Mechanistically, activation of ERK1/2 requires phosphorylation by its upstream protein kinase MEK (Mao et al, 2004 ) which is in turn regulated by Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuron-specific Ras activator required for subsequent activation of ERK1/2 by either D1R or NMDA receptors (Fasano et al, 2009 , 2010 ; Cerovic et al, 2015 ).…”

Section: Signal Transduction Via the D1rmentioning

confidence: 99%

“…Upon activation, phosphorylated ERK1/2 can translocate to the nucleus, a response well-documented in striatal neurons (Sgambato et al, 1998 ). In cultured striatal neurons, both PKA and ERK1/2 are activated in the nucleus with similarly rapid kinetics following D1R activation (Jones-Tabah et al, 2021 ). The nuclear targets of ERK1/2 include transcription factors such as CREB and Elk-1 (Valjent et al, 2001 ), and nuclear protein kinases such as MSK1 and RSK (Xing et al, 1996 ).…”

Section: Signal Transduction Via the D1rmentioning

confidence: 99%

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The Signaling and Pharmacology of the Dopamine D1 Receptor

Jones-Tabah

Mohammad

Paulus

et al. 2022

Front. Cell. Neurosci.

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The dopamine D1 receptor (D1R) is a Gαs/olf-coupled GPCR that is expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, and cognitive processes. Although the D1R was initially identified as a promising drug target almost 40 years ago, the development of clinically useful ligands has until recently been hampered by a lack of suitable candidate molecules. The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders. To develop better therapeutics, advances in ligand chemistry must be matched by an expanded understanding of D1R signaling across cell populations in the brain, and in disease states. Depending on the brain region, the D1R couples primarily to either Gαs or Gαolf through which it activates a cAMP/PKA-dependent signaling cascade that can regulate neuronal excitability, stimulate gene expression, and facilitate synaptic plasticity. However, like many GPCRs, the D1R can signal through multiple downstream pathways, and specific signaling signatures may differ between cell types or be altered in disease. To guide development of improved D1R ligands, it is important to understand how signaling unfolds in specific target cells, and how this signaling affects circuit function and behavior. In this review, we provide a summary of D1R-directed signaling in various neuronal populations and describe how specific pathways have been linked to physiological and behavioral outcomes. In addition, we address the current state of D1R drug development, including the pharmacology of newly developed non-catecholamine ligands, and discuss the potential utility of D1R-agonists in Parkinson's Disease and cognitive impairment.

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Section: Signal Transduction Via the D1rmentioning

confidence: 78%

Section: Signal Transduction Via the D1rmentioning

confidence: 99%

Section: Signal Transduction Via the D1rmentioning

confidence: 99%

Section: Signal Transduction Via the D1rmentioning

confidence: 99%

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The Signaling and Pharmacology of the Dopamine D1 Receptor

Jones-Tabah

Mohammad

Paulus

et al. 2022

Front. Cell. Neurosci.

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“…Single cell analyses allow to better understand the variability that shapes the population as a whole. In line with this, we applied two single cell analytical pipeline to dissect biosensor data collected using the Opera Phenix automated high content microscope from Perkin Elmer or the Zeiss Axio Observer (43). The Opera Phenix was used to track ERK 1/2 and PKA signalling overtime while the faster imaging speed of the Zeiss Axio Observer was used to collect calcium handling data.…”

Section: Resultsmentioning

confidence: 99%

Effective use of genetically-encoded optical biosensors for profiling signalling signatures in iPSC-CMs derived from idiopathic dilated cardiomyopathy patients

Bourque

Derish

Hawey

et al. 2022

Preprint

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Dilated cardiomyopathy (DCM) is a cardiovascular condition that develops when the left ventricle of the heart enlarges, compromising its function and diminishing its capacity to pump oxygenated blood throughout the body. After patients are diagnosed with DCM, disease progression can lead to heart failure and the need for a heart transplantation. DCM is a complex disease where underlying causes can be idiopathic, genetic, or environmental. An incomplete molecular understanding of disease progression poses challenges for drug discovery efforts as effective therapeutics strategies remain elusive. Decades of research using primary cells or animal models have increased our understanding of DCM, but has been hampered due to the inaccessibility of human cardiomyocytes, to model cardiac disease, in vitro, in a dish. Here, our goal is to leverage patient-derived hiPSC-CMs and to combine them with biosensors to understand how cellular signalling is altered in DCM. With high sensitivity and versatility, optical biosensors represent the ideal tools to dissect the molecular determinants of cardiovascular disease, in an unbiased manner and in real-time at the level of single cells. By characterizing the pathobiology of dilated cardiomyopathy in a patient-specific manner using high content biosensor-based assays, we aim to uncover personalized mechanisms for the occurrence and development of DCM and as a pathway to development of personalized therapeutics.

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