About

Dr. Sabrina Diano earned both her Doctor of Biology and PhD degrees from the University of Naples “Federico II” in Naples, Italy. She moved to Yale University in 1994 to pursue her interest in metabolism regulation, where she was awarded a PhD in Physiology in 1999 based on studies that combined neuroendocrinology and mitochondrial biology to explore the brain’s role in energy and glucose metabolism. She joined the Yale faculty in 2000, rising through the academic ranks before joining Columbia University in September 2020 to lead the Institute of Human Nutrition. Her research investigates how the brain regulates energy balance and glucose homeostasis, employing interdisciplinary methods such as molecular biology, neuroanatomy, biochemistry, electrophysiology, chemogenetics, and behavioral studies in rodent models. Her lab explores how brain cells sense nutrients and communicate metabolic signals, aiming to uncover cellular and molecular mechanisms that enable the brain to maintain metabolic balance and how disruptions contribute to obesity, type 2 diabetes, and related metabolic disorders. Additionally, her current work examines how metabolic dysfunction may contribute to neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as psychiatric conditions including anxiety and depression. Dr. Diano’s studies on metabolism regulation have received international recognition, including the Helmholtz Diabetes Award in 2018 and being named a Fellow of the American Association for the Advancement of Science. Her research, funded by the NIH and published in leading scientific journals, provides crucial insights into the mechanisms underlying obesity, diabetes, and metabolic syndrome, and sheds light on the metabolic dimensions of neurological and psychiatric diseases.

Research topics

• Biochemistry
• Biology
• Chemistry
• Cell biology
• Biophysics
• Pharmacology
• Genetics
• Stereochemistry
• Neuroscience
• Medicine
• Computational biology

Selected publications

• CD33 forms functional dimers on cell surface to modulate Alzheimer risk

  Alzheimer s & Dementia · 2025-12-01

  articleOpen access

  Abstract Background The sialic‐acid binding immunoglobulin‐like lectin 3 receptor (Siglec‐3 / CD33) is one of the highly associated AD risk genes. Previous studies revealed that the non‐coding AD‐risk alleles (rs3865444 and rs12459419) are associated with increased total levels of CD33 expression and a higher relative expression of the long CD33 M splice form. However, the molecular basis of the immuno‐inhibitory function of CD33 remains unclear. Method To confirm the presence of CD33 dimers, we conducted multiple experiments. Blue Native Gel electrophoresis and co‐immunoprecipitation assays were used to detect CD33 bands corresponding to the expected molecular weights. Flow cytometry with specific antibodies was performed to quantify cell‐surface CD33. Additionally, single‐molecule fluorescence resonance energy transfer (smFRET) combined with TIRF imaging was employed to visualize CD33 dimers on the cell surface. Furthermore, Western Blotting of phosphorylation of CD33 and its downstream molecule were performed to verify if the dimers were functional. Result Biochemical analyses demonstrated that CD33 M and CD33 m can form homodimers or heterodimers. Flow cytometry confirmed that CD33 M isoforms are selectively trafficked to the cell surface, while smFRET imaging verified the presence of dimers on the cell surface. The elevation of the CD33 pathway following stimulation with CD33‐specific ligands provided evidence that CD33 M homodimers are functional. Conclusion This study reveals the critical role of CD33 M in AD pathology by elucidating its molecular mechanisms. We provide direct evidence that CD33 M and CD33 m isoforms can form both homodimers and heterodimers. However, only CD33 M isoforms are preferentially trafficked to the cell surface and form functional dimers. These findings advance our understanding of the molecular basis of CD33's immuno‐inhibitory function and offer new insights into its involvement in AD risk, potentially paving the way for the development of targeted therapeutic strategies.

  PublisherOA PDFDOI

• BPS2025 - Elucidating the molecular logic of a metabotropic glutamate receptor heterodimer

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

• Complex G-protein signaling of the adhesion GPCR, ADGRA3

  Journal of Biological Chemistry · 2025-03-22 · 2 citations

  articleOpen access

  ADGRA3 (GPR125) is an orphan adhesion G protein-coupled receptor (aGPCR) involved in planar cell polarity, primarily through recruitment of the signaling components disheveled (DVL) during vertebrate gastrulation and discs large homolog 1, implicated in cancer. Limited knowledge exists of the canonical G protein-coupled receptor pathways downstream of ADGRA3. Here, we employed a series of human cell line-based signaling assays to gain insight into the G protein-mediated signaling of ADGRA3. We designed ADGRA3 constructs based on transcript variant analysis in publicly available human liver and brain RNA-seq datasets. Cleavage in the GPCR autoproteolysis site (GPS) is an aGPCR hallmark; thus, we generated a truncated ADGRA3 (C-terminal fragment, CTF) corresponding to a potential cleavage at the GPS. We found low-level activation of Gi and Gs by ADGRA3 and slightly more by its CTF. As the N terminus of the CTF constitutes a class-defined tethered agonist (so-called stachel peptide), we removed the initial three amino acids of the CTF. This resulted in abrogated G protein-mediated signaling, as observed for other aGPCRs. Due to the central role of ADGRA3 in planar cell polarity signaling through DVL recruitment, we investigated the G-protein signaling in the absence of DVL1-3 and found it sustained. No transcriptional activation was observed in an assay of downstream β-catenin activity. Collectively, this establishes classical G protein-mediated signaling for ADGRA3.

  PublisherOA PDFDOI

• Identification of a Lipid-Exposed Extrahelical Binding Site for Positive Allosteric Modulators of the Dopamine D₂ Receptor

  ACS Chemical Neuroscience · 2025-05-15 · 3 citations

  articleOpen access

  Recently, the first small-molecule positive allosteric modulators (PAMs) of the dopamine D2 receptor (D2R) were identified. The more potent PAM potentiated the effects of D2R signaling in vitro and in an in vivo model predictive of anti-Parkinson’s efficacy. We reveal, based on the results of our site-directed mutagenesis and molecular dynamics experiments, that this scaffold binds to a hitherto unexploited lipid-exposed extrahelical allosteric site in the D2R that lies in a cleft toward the intracellular aspect of the D2R defined by residues in transmembrane domains 1 and 7 and helix 8. By binding to this site, the PAM acts to potentiate the binding affinity of efficacious agonists, such as dopamine. Our simulations suggest that the PAM achieves this effect by stabilizing an active-like conformation of the receptor, similar to the G protein-bound state with TM5 and the tyrosine toggle switch playing the major role.

  PublisherDOI

• Parallel stopped-flow interrogation of diverse biological systems at the single-molecule scale

  Nature Methods · 2025-12-02 · 3 citations

  articleOpen access

  Single-molecule imaging techniques have provided unprecedented insights into functional changes in composition and conformation across diverse biological systems. As with other biophysical methods, single-molecule fluorescence and Förster resonance energy transfer investigations are typically limited to examination of one sample at a time. Consequently, experimental throughput is restricted, and experimental variances are introduced that can obscure functional distinctions in closely related systems. Here, to address these limitations, we introduce parallel rapid exchange single-molecule fluorescence and single-molecule Förster resonance energy transfer to enable simultaneous steady-state and pre-steady-state interrogations of diverse systems. Using this approach, we elucidate the timing of distinct conformational events underpinning β-arrestin1 activation, unmask antibiotic-induced impacts on messenger RNA decoding fidelity and demonstrate that endogenously encoded ribosomal RNA sequence variation modulates antibiotic sensitivity. This generalizable and scalable method promises to broaden the scope and reproducibility of quantitative single-molecule interrogations of biomolecular function.

  PublisherOA PDFDOI

• Chronic administration of methocinnamox, a mu-opioid receptor antagonist, reduces hedonic response without impacting motivation in mice

  Psychopharmacology · 2025-05-09

  article
  PublisherDOI

• Habenular μ-opioid receptor knockout and chronic systemic receptor blockade promote negative affect and heighten nociceptive sensitivity

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-03

  preprintOpen accessSenior authorCorresponding

  The μ-opioid receptor (MOR), a subtype of opioid G protein-coupled receptor, is expressed in multiple brain circuits and is particularly enriched in the habenula, a small epithalamic structure implicated in aversive states. MOR dysfunction has been linked to several psychiatric and nociceptive disorders. Identifying the key brain regions mediating the behavioral consequences of disrupted MOR signaling can shed light on the role of the opioid system in mood and pain regulation. In this study, we administered methocinnamox (MCAM), a long-acting, pseudo-irreversible MOR antagonist, acutely or chronically to adult C57BL/6J mice. A comprehensive behavioral battery was used to assess affective, social, and pain behavior. A single MCAM administration (10 mg/kg, s.c.) did not alter baseline behavior, but blocked opioid-induced analgesia, suggesting that basal μ-opioid tone does not contribute to these behaviors. In contrast, chronic MCAM administration (10 mg/kg, s.c., 3x/week for 4 weeks) led to increased anxiety-like behavior and decreased sociability, as well as enhanced mechanical allodynia and thermal hyperalgesia. Remarkably, selective knockout of habenular MORs in adult Oprm1fl/fl mice reproduced key features of the chronic MCAM phenotype, including anxiety-like behavior and mechanical hyperalgesia. Together, these findings reveal that sustained inhibition of MOR signaling disrupts affective and nociceptive processing and highlight the habenula as a node mediating key behavioral deficits of disrupted opioid signaling.

  PublisherOA PDFDOI

• BPS2025 - Conformational divergence between β-arrestin1 and β-arrestin2 revealed by temperature replica-exchange MD simulations

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• Conformational dynamics of the active state of β-arrestin 1

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-14

  preprintOpen access

  β-arrestins (βarr) regulate the signaling and trafficking of G protein-coupled receptors (GPCRs) in numerous physiological processes and have been implicated in various diseases. Structural and kinetic insights into how ligand-mediated GPCR activation drives βarr coupling and activation remain limited, with the binding mechanism of the phosphorylated GPCR C-terminal tails, such as that of the vasopressin receptor-2 (V2Rpp), and the conformation of the entire βarr tail in the active state still unknown. Here, we simulated both the basal and V2Rpp-bound states of βarr1 with temperature replica-exchange molecular dynamics (TREMD) simulations to probe the activation mechanism of βarr1. Compared to conventional MD, our TREMD simulations, employing an unprecedented 200-replica setup, significantly broadened conformational sampling while preserving the basal state. Our analysis showed that, without the bound Fab30 antibody fragment, the main body of V2Rpp-bound βarr1 tended to transition toward the basal conformation; however, binding of V2Rpp in the N-domain groove allosterically oriented the finger loop to point upward for core engagement with a GPCR. Furthermore, V2Rpp dissociation events suggest that its binding involves a sliding movement along the N-domain groove, during which its phosphorylated residues p3 and p4 transiently occupy the S5 site to facilitate repositioning of p5 into the S5 site, thereby triggering a zippering process of p1 to p3. The dynamic 62-residue βarr1 tail explored a vast conformational space, forming transient secondary structures, and could favorably anchor on the main body's back side and within the central crest crevice. These findings elucidate key mechanistic steps underlying βarr1 activation.

  PublisherOA PDFDOI

• N-terminal fragment shedding contributes to signaling of the full-length adhesion receptor ADGRL3

  Journal of Biological Chemistry · 2025-01-10 · 3 citations

  articleOpen accessSenior author

  and showed a much lower level of spontaneous NTF shedding, approximately 20% of that observed for WT receptor. This loss of spontaneous NTF shedding likely explains its diminished signaling activity. These findings suggest that TA-mediated signal transduction by full-length ADGRL3 requires removal of its NTF.

  PublisherDOI

Recent grants

• Probing mechanisms of amphetamine action at plasma membrane and vesicular transporters in vitro and in vivo

  NIH · $2.7M · 2017–2023

• NIH Grant R01GM109879

  NIH · $1.1M · 2019

• NIH Grant R01DA011495

  NIH · $2.7M · 2008

• NIH Grant R01DA017293

  NIH · $4.9M · 2016

• NIH Grant R21DA014942

  NIH · $327k · 2003

Frequent coauthors

• Lei Shi

  National Institutes of Health

  366 shared

• Prashant Donthamsetti

  Vanderbilt University

  169 shared

• Thijs Beuming

  Schrodinger (United States)

  165 shared

• Amy Hauck Newman

  National Institute on Drug Abuse

  160 shared

• Yang Han

  The University of Texas Health Science Center at Tyler

  160 shared

• Lihua Duan

  Central South University

  155 shared

• Matthias Quick

  Columbia University Irving Medical Center

  151 shared

• Mayako Michino

  Tri-Institutional Therapeutics Discovery Institute

  121 shared

Labs

• Diano LabPI

Education

• M.D.

  Columbia University

• Ph.D.

  Columbia University

Awards & honors

• Lieber Professor of Experimental Therapeutics in Psychiatry