Ask the Author: DETQ as a tool for tuning dopamine sensors

Ask the Author: DETQ as a tool for tuning dopamine sensors

It’s time for another edition of Ask the Author – our interview series where we talk directly to the scientists behind exciting new research. In each article, we ask the authors of cutting-edge papers to share the story behind their discoveries, the challenges they faced, and what their findings mean for the wider scientific community.

At Hello Bio, we’re passionate about making innovative tools and compounds accessible to researchers worldwide. Through Ask the Author, we aim to give you a behind-the-scenes look at how these tools are being used to advance neuroscience and beyond.

In this edition, we caught up with Marie Labouesse, co-first author of a recent paper in Nature Communications, and Tommaso Fava of the Patriarchi Lab at the University of Zurich, who is now building upon that work. Their research introduces DETQ as a powerful way to tune dopamine imaging sensitivity, and we’re proud to be the first supplier of DETQ, making this exciting tool available to labs around the world!

★ Read the paper: A chemogenetic approach for dopamine imaging with tunable sensitivity ★

The Patriarchi Lab develops optogenetic tools to help elucidate brain mechanisms underlying animal behavior and neuropsychiatric disorders.

Could you briefly introduce yourselves and your roles in this study?

ML: My name is Marie Labouesse, I am one of the four co-first authors on the DETQ paper, together with Maria Wilhelm, Zacharoula Kagiampaki and Andrew Yee. I worked in the Patriarchi lab as a senior scientist.

TF: I’m Tommaso Fava, currently a research assistant in the Patriarchi lab, hopefully soon to start a PhD. I didn’t author the DETQ paper but I’m now working on follow-ups.

What motivated your team to tackle the challenge of improving dopamine imaging sensitivity?

TF: We wanted to tackle the fact that dopamine sensors struggle with low tonic signals. The motivation was to make tonic levels visible without redesigning sensors.

ML: Like Tommaso said, it was all about capturing those low tonic signals. Before joining the Patriarchi lab, I worked on dopamine biology. I wanted to measure dopamine signals in regions like the prefrontal cortex where dopamine is known to be important (e.g. for cognition) but it had been difficult to measure with good resolution.

Your study introduces DETQ as a tool to boost the sensitivity of dopamine sensors. What was the main limitation you were trying to overcome?

TF: The main limitation was the fixed affinity of sensors, they miss tonic dopamine. A way to tune that on demand was wanted.

ML: Many labs already had workflows to measure strong dopamine signals with the existing dopamine sensors (like dLight). We apply DETQ as an on/off switch to boost the sensitivity of those existing sensors temporarily and detect more subtle variations in dopamine levels.

Can you explain, in simple terms, how DETQ enhances dopamine detection and why this matters for studying tonic vs. phasic release?

TF: DETQ is an intracellularly acting PAM (Positive Allosteric Modulator) for the D1 receptor scaffold. It stabilizes the active conformation of the receptor when dopamine is bound and the sensor’s apparent affinity for dopamine increases (left-shift in EC₅₀). It makes D1- based sensors more sensitive to dopamine, so you can detect faint tonic levels and still capture phasic bursts.

ML: The important trick here is that DETQ binds strongly to the human D1 receptor (and therefore the dLight dopamine sensor), but because of a few mutations, it binds with poor affinity to the mouse D1 receptor. In our hands we did not see effects of DETQ on mouse physiology or behavior, at least at doses we tested. The idea came in the first place via a collaboration with Kjell Svensson at Eli Lilly. He and his colleagues were developing an allosteric modulator for the human D1 receptor to treat dementia. They shared DETQ with us as a tool compound to see whether we could detect DETQ binding on our dopamine sensor (dLight), which is essentially a modified human D1 receptor with a GFP tag on it.

The paper shows a stable window of potentiation without affecting behavior. Why is that important for researchers?

TF: The stable ~31-minute potentiation window is very important, it boosts sensitivity without altering animal behavior, so you can trust the signals, we want to observe behaviour not causing it.

ML: We tried to modify the sensor to get a longer stable window, but did not manage at the time. We need more rounds of engineering to achieve that goal.

What was the most surprising or exciting discovery you made using DETQ?

TF: The most exciting finding was observing tonic differences and single-trial phasic events that were undetectable before… essentially pulling hidden signals out of noise.

ML: …including in the prefrontal cortex.

This was clearly a big team effort with many co-authors involved. Could you tell us how the different members of your group contributed, and why this kind of teamwork was important for the project?

TF: This needed many skills: chemistry, cell assays, slice physiology, in vivo imaging, behavior. That teamwork made the findings solid across models, showing that the system is nicely working in vitro as in vivo.

ML: The teamwork was definitely my favorite part of the project. You learn so much from others.

How do you see researchers using DETQ in their own experiments?

TF: Researchers can use DETQ to temporarily “turn up the gain” of DA sensors for tonic signals or single-trial detection, especially in the cortex. Labs can apply DETQ systemically or locally to boost sensitivity of D1-based sensors (like dLight) during a defined time window, use the time-boxed potentiation to probe tonic baseline differences before/after manipulations and improve single-trial detection of subtle, behavior-evoked phasic events.

ML: …and this can be used both in vivo but also in vitro (e.g. neurons) or ex vivo (e.g. brain slices)

Could this approach be extended to other neurotransmitter sensors beyond dopamine?

TF: Yes, certainly, the idea is general. In fact, if a genetically encoded sensor is based on a GPCR that has a selective PAM, the same chemogenetic principle should apply, theoretically. As long as the PAM is selective and pharmacologically safe in your model, you can “make more sensitive” other GPCR-based sensors in the same way.

ML: Agreed. We got lucky that DETQ had poor affinity on the mouse D1 receptor; this made our life easier. In other systems it may be different. In principle one could also do biochemical engineering to make PAMs that fit the right profile.

What does it mean to you that Hello Bio will be the first to supply DETQ (at a reasonable price!) to the neuroscience community?

TF: This is important because ready availability and a standard supplier make the technique accessible and reproducible in all laboratories. By making DETQ available as a product for researchers, Hello Bio makes it easy for groups to order and try the approach themselves without custom syntheses. Wider access will accelerate its adoption and make it easier to compare results between laboratories.

ML: Agreed. And it was great to connect with some of the Hello Bio team at the FENS conference last year and discuss the option of doing this custom synthesis.

Looking ahead, what excites you most about the future of chemogenetics and dopamine research?

TF: What excites me most is this new field of “shifting” sensors from being static reporters to dynamic, tunable tools. With PAMs like DETQ, we can directly adjust sensitivity in vivo.

ML: The whole field is exciting and fast-paced. The D1-PAM is a great and handy trick. I also find very cool the other ways that labs are using to boost dopamine imaging sensitivity (new sensors without chemogenetics, FLIM, etc.)

What is DETQ?

DETQ is a potent and selective dopamine D1 receptor positive allosteric modulator (Kb = 11.4nM and EC50 = 5.8nM in human D1 receptors) suitable for use with genetically encoded dopamine sensors to enhance sensitivity. 

What is it used for?

When used with the dLight1.3b genetically encoded dopamine sensor, DETQ administration leads to an 8-fold increase in dopamine sensitivity (2µM to 244nM) with a Kb of 54nM. Due to a 30-fold lower affinity for rodent D1 receptors (Mouse D1: Kb = 312nM) compared to human (Kb = 11.4) this makes DETQ suitable for chemogenetic modulation of human based dopamine sensors in rodents. DETQ reverses reserpine induced locomotor deficits alongside increasing PFC histamine and acetylcholine concentrations in human D1 expressing mice.

Storage: -20°C | Solubility: Soluble in DMSO | Product code: HB15406

At Hello Bio, we’re proud to support scientists with affordable, high-quality tools that make discoveries like these possible. We’re especially excited to be the first to supply DETQ, so that labs around the world can benefit from this innovative compound.

★ Explore DETQ and our full range of trusted dopamine and chemogenetic ligands ★

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