The chemical tools for imaging dopamine release

Post, Michael R.; Sulzer, David

doi:10.1016/j.chembiol.2021.04.005

Cited by 34 publications

(31 citation statements)

References 169 publications

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“…Accurate measurements of cytoplasmic DA in intact pre- or postsynaptic neurons have been challenging due to lack of sensitivity of most analytical methods and their effects on cell viability ( Chang et al, 2021 ; Olefirowicz and Ewing, 1990 ; Post and Sulzer, 2021 ). However, given that DA is present at high millimolar concentrations within the synaptic vesicles ( Omiatek et al, 2013 ; Zhang et al, 2020 ), it is likely that rapid uptake of DA post release will result in high cytoplasmic DA concentrations.…”

Section: Discussionmentioning

confidence: 99%

The organic cation transporter 2 regulates dopamine D1 receptor signaling at the Golgi apparatus

Puri

Romano

Lin

et al. 2022

eLife

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Dopamine is a key catecholamine in the brain and the kidney, where it is involved in a number of physiological functions such as locomotion, cognition, emotion, endocrine regulation and renal function. As a membrane impermeant hormone and neurotransmitter, dopamine is thought to signal by binding and activating dopamine receptors, members of the G protein couple receptor (GPCR) family, only on the plasma membrane. Here, using novel nanobody-based biosensors, we demonstrate for the first time that the dopamine D1 receptor (D1DR), the primary mediator of dopaminergic signaling in the brain and kidney, not only functions on the plasma membrane but becomes activated at the Golgi apparatus in the presence of its ligand. We present evidence that activation of the Golgi pool of D1DR is dependent on Organic Cation Transporter 2 (OCT2), a dopamine transporter, providing an explanation for how the membrane impermeant dopamine accesses subcellular pools of D1DR. We further demonstrate that dopamine activates Golgi-D1DR in murine striatal medium spiny neurons (MSN) and this activity depends on OCT2 function. We also introduce a new approach to selectively interrogate compartmentalized D1DR signaling by inhibiting Gas coupling, using a nanobody-based chemical recruitment system. Using this strategy, we show that Golgi-localized D1DRs regulate cAMP production and mediate local protein kinase A activation. Together, our data suggest that spatially compartmentalized signaling hubs are previously unappreciated regulatory aspects of D1DR signaling. Our data provide further evidence for the role of transporters in regulating subcellular GPCR activity.

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Section: Discussionmentioning

confidence: 99%

The organic cation transporter 2 regulates dopamine D1 receptor signaling at the Golgi apparatus

Puri

Romano

Lin

et al. 2022

eLife

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“…Accurate measurements of cytoplasmic DA in intact pre-or post-synaptic neurons have been challenging due to lack of sensitivity of most analytical methods and their effects on cell viability (88)(89)(90). However, given that DA is present at high millimolar concentrations within the synaptic vesicles (91,92), it is likely rapid uptake of DA post release will result in high cytoplasmic concentrations.…”

Section: Discussionmentioning

confidence: 99%

The OCT2 Transporter Regulates Dopamine D1 Receptor Signaling at the Golgi Apparatus

Puri¹,

Quynh

et al. 2020

Preprint

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G protein-coupled receptors (GPCRs) are the largest family of membrane receptors expressed in humans. It has been traditionally thought that GPCRs can only signal on the plasma membrane, where receptors are activated upon binding of external cues. However, recent work has demonstrated that, in several cases, subcellularly-localized GPCRs are also activated upon the presence of external cues resulting in downstream signaling pathways. Whether subcellular activation of GPCRs is limited to subsets of GPCRs or is a general aspect of GPCR signaling is not known. Additionally, establishing GPCR signaling from subcellular compartments is the first step in unraveling the physiological consequences of compartmentalized signaling for each GPCR family member. Here, using novel nanobody-based biosensors, we demonstrate that dopamine D1 receptor (D1DR), the primary mediator of dopaminergic signaling in the brain and kidney, is activated at both the plasma membrane and the Golgi apparatus upon the presence of its ligand. Interestingly, we found that activation of the Golgi pools of D1DRs is dependent on Organic Cation Transporter 2 (OCT2), a low affinity dopamine transporter, providing an explanation for how dopamine, a membrane impermeant ligand, accesses subcellular pools of D1DR. We also show that Golgi-localized D1DRs regulate local cAMP production and mediate protein kinase A activation at the Golgi membranes. Together, our data suggest that spatially compartmentalized signaling hubs are previously unappreciated regulatory aspects of D1DR signaling. Our data also provide further evidence for the role of transporters in regulating subcellular GPCR activity.

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“…Chemical dyes and nanomaterials are rich resources for developing new fluorescence probes. Fluorescent false neurotransmitters (FFN) are synthetic fluorescent neurotransmitter analogs that can trace the accumulation and release of dopamine, norepinephrine, and serotonin with single synapse resolution (Dunn et al, 2018;Henke et al, 2018;Post and Sulzer, 2021). FFNs undergo vesicular loading and release with native neurotransmitters by binding to specific neurotransmitter transporters, such as VMAT2, DAT, NET, and SERT (Gubernator et al, 2009;Henke et al, 2018).…”

Section: Non-genetically Encoded Neurochemical Probesmentioning

confidence: 99%

Letting the little light of mind shine: Advances and future directions in neurochemical detection

Tjahjono

Jin

Hsu

et al. 2022

Neuroscience Research

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The chemical tools for imaging dopamine release

Cited by 34 publications

References 169 publications

The organic cation transporter 2 regulates dopamine D1 receptor signaling at the Golgi apparatus

The organic cation transporter 2 regulates dopamine D1 receptor signaling at the Golgi apparatus

The OCT2 Transporter Regulates Dopamine D1 Receptor Signaling at the Golgi Apparatus

Letting the little light of mind shine: Advances and future directions in neurochemical detection

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