Lauren Slosky

Ventral tegmental area GABA neurons integrate positive and negative valence - Nature Communications The role of ventral tegmental area GABA neurons in behavior is unclear. Here, authors show that VTA GABA but not dopamine neurons integrate positive and negative valence to encode motivational conflic...

So excited to see our latest paper out today in @natcomms.nature.com! Studies led by the amazing @margestelzner.bsky.social www.nature.com/articles/s41.... VTA GABA neurons have a unique role in economic decision making - they integrate reward seeking motivation and the current cost of seeking

The synaptic ectokinase VLK triggers the EphB2–NMDAR interaction to drive injury-induced pain Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families but the functional role of these kinases is underexplored. We find that the presynaptic release of the t...

Big new paper from us published yesterday: The synaptic ectokinase VLK triggers the EphB2–NMDAR interaction to drive injury-induced pain
www.science.org/doi/10.1126/...
Led by @hajisciencebaji.bsky.social in my lab and a wonderful collaboration with Matthew Dalva's lab at Tulane

Big congratulations to @kelseyperson.bsky.social and @valeriarobleto.bsky.social on receiving SfN Trainee Professional Development Awards. 🎉 So grateful to @sfn.org for this support!

Lots of cool stuff going on. Come to visit, and stay to get your fill of dose-response curves and learn more than you ever (knew you) wanted to know about neurotensin receptor 1!! 🤓 📈

#SfN2025 here we come! I am thrilled to be joined at the Society for Neuroscience meeting this year by Madelyn Moore, @kelseyperson.bsky.social, @valeriarobleto.bsky.social, and Crystal Lemchi. If you are in San Diego for the conference, please stop by to say hi! 👋 🧪🧠🟦

Multiple Allosteric Sites Allow for Synergistic Enhancement of GPCR Signaling https://www.biorxiv.org/content/10.1101/2025.10.21.683604v1

Thank you SBP for the wonderful highlight! And thank you @behnoushhajian.bsky.social for the beautiful artwork! ✨

Scientists at Sanford Burnham Prebys, the University of Minnesota and Duke University report in Nature that “biased modulators” can target GPCRs more precisely—expanding potential drug targets and reducing side effects. www.nature.com/articles/s41...

'Molecular glues' and 'bumpers' offer new hope for precision medicines New research led by the University of Minnesota Medical School demonstrates that molecules acting as "molecular bumpers" and "molecular glues" can rewire G protein-coupled receptor (GPCR) signaling, turning the cell's busiest receptors into precision tools—opening the door to a new generation of safer, smarter medicines.

Newly designed molecules acting as "molecular glues" and "bumpers" can selectively rewire GPCR signaling, offering a pathway to more precise and potentially safer medicines. doi.org/g98xfp

Molecular ‘glues’ and ‘bumpers’ on receptors can bias signalling inside the cell Small molecules that bind to G-protein-coupled receptors’ intracellular pockets can be designed to have pathway-selective effects.

Wow! Thank you @nature.com for highlighting our recent work in this nice Research Brief! 🧪🧠🟦

A broad overview and glimpse behind the making of the paper 👨‍🍳👩‍🍳

A big thank you to John McCorvy for weighing in!!

Brief 👉 www.nature.com/articles/d41...

Paper 👉 www.nature.com/articles/s41...

Designing allosteric modulators to change GPCR G protein subtype selectivity - Nature Studies of the G-protein-coupled receptor NTSR1 show that the G protein selectivity of this receptor can be modified by small molecules, enabling the design of drugs that work by switching receptor subtype preference.

Nature research paper: Designing allosteric modulators to change GPCR G protein subtype selectivity

go.nature.com/49jaBQS

🎉 thanks @jwietek.bsky.social!!

Thank you Nina!!

Thanks Ben!!

Thank you, Tom!!

Yay! Really psyched for the team here. Thank you, Zoe!!

Led by superstar students @kelseyperson.bsky.social and Maddi Moore with @valeriarobleto.bsky.social. This entire line of investigation was made possible by Steve Olson and his med chem group @sbpdiscovery.bsky.social. Hugely grateful to our entire team at UMN and beyond!

Why are we excited? This is a strategy for changing the cellular consequences of receptor activation and achieving truly biased, G protein-subtype-selective compounds that is broadly applicable to the GPCR superfamily. So many new possibilities!

These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.

Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.

Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator. WHAT. 🤯

Remarkably, small modifications to the SBI-553 scaffold produce compounds with qualitatively different G protein activation profiles! Some compounds behaved as predicted – like this one 🎳

Can this compound’s G protein selectivity profile be changed by modifying its structure? Yes! Based on these models, we compiled a series of SBI-553 derivatives and screened them in a high-dimensional SAR study including representative G protein family members and β-arrestin.

G protein homology models based on this alternative, shallow-binding conformation did a great job at explaining SBI-553’s G protein subtype-specific effects on NT and its own agonism.

Why does this work? The G protein C-terminus needs to adopt a new binding position to accommodate the compound. SBI-553 blocks G protein binding determinants, promoting association with select G protein subtypes for which a shallow-binding conformation is energetically favorable.

If not through β-arrestin, where does the block come from? Subtype-selective steric exclusion. Sensitivity to SBI-553 antagonism is determined by the primary structure of the G protein C-terminus and can be changed by swapping just the 5 C-term amino acids of these G proteins.

How does it do this? SBI-553 selectively fully antagonizes NTSR1-Gq/11 coupling. No β-arrestin needed for its G protein antagonism!

This biased allosteric modulator (BAM) biases NTSR1 not only toward β-arrestin, but also toward alternative G protein signaling, switching NTSR1 from a Gq/11 preferring receptor to a G12/13 preferring receptor.

Pretty cool 🧪🧠🟦

When NT and SBI-553 are applied in combination, SBI-553 antagonizes NT-induced activation of some G proteins and promotes NT-induced activation of others. Some strikingly transducer-specific effects here!

Interestingly, we found that SBI-553 acts not only as a full β-arrestin agonist at NTSR1 but also a weak G protein agonist for a subset of G proteins (e.g., G12/13, Go).