Joshua Levitz
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View article: MRAP2 potentiates GPCR signaling by conserved mechanisms that are disrupted by obesity-associated genetic variants
MRAP2 potentiates GPCR signaling by conserved mechanisms that are disrupted by obesity-associated genetic variants Open
Accessory proteins such as members of the melanocortin-2 receptor accessory protein family (MRAP) have been described to interact with and regulate the signaling of diverse G protein-coupled receptors (GPCRs), however, surprisingly little …
View article: Environmental and genetic risk factors of depression converge on neuronal dysfunction driven by changes in cholesterol homeostasis
Environmental and genetic risk factors of depression converge on neuronal dysfunction driven by changes in cholesterol homeostasis Open
Major depressive disorder (MDD) is a complex, multifactorial neuropsychiatric disorder influenced by both genetic and environmental factors, but how these factors impact human neuronal function remains unclear. Using a highly defined human…
View article: Developing HaloTag and SNAP‐Tag Chemical Inducers of Dimerization to Probe Receptor Oligomerization and Downstream Signaling
Developing HaloTag and SNAP‐Tag Chemical Inducers of Dimerization to Probe Receptor Oligomerization and Downstream Signaling Open
Controlling protein–protein interactions is critical for dissecting signaling pathways, especially those initiated by ligand‐receptor interactions, which alter receptor oligomerization and drive downstream signaling cascades. Traditional m…
View article: Structural Diversity and Dynamics of Metabotropic Glutamate Receptor/Beta-Arrestin Coupling
Structural Diversity and Dynamics of Metabotropic Glutamate Receptor/Beta-Arrestin Coupling Open
Beta-arrestins (β-arrs) are cytosolic proteins which mediate G protein-coupled receptor (GPCR) desensitization, endocytosis, and signaling. Despite the widespread physiological roles of β-arr coupling, the molecular basis of GPCR/β-arr int…
View article: An opioid efficacy switch for reversible optical control of peripheral analgesia
An opioid efficacy switch for reversible optical control of peripheral analgesia Open
The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders or, even, lethal overdose. The systemic…
View article: Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia
Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia Open
Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments as a complement to opioid-based treatments. Here, we show in male and female mice that enhancing l…
View article: Red and far-red cleavable fluorescent dyes for self-labelling enzyme protein tagging and interrogation of GPCR co-internalization
Red and far-red cleavable fluorescent dyes for self-labelling enzyme protein tagging and interrogation of GPCR co-internalization Open
SNAP- and Halo-tagged cell surface receptors are labelled, internalized and stripped from the extracellular pool using the reductant MESNA, allowing for two-color receptor co-internalization measurements and quantification.
View article: The MRAP2 accessory protein directly interacts with melanocortin-3 receptor to enhance signaling
The MRAP2 accessory protein directly interacts with melanocortin-3 receptor to enhance signaling Open
The central melanocortin system links nutrition to energy expenditure, with melanocortin-4 receptor (MC4R) controlling appetite and food intake, and MC3R regulating timing of sexual maturation, rate of linear growth and lean mass accumulat…
View article: A one-step protocol to generate impermeable fluorescent HaloTag substrates for<i>in situ</i>live cell application and super-resolution imaging
A one-step protocol to generate impermeable fluorescent HaloTag substrates for<i>in situ</i>live cell application and super-resolution imaging Open
Communication between cells is largely orchestrated by proteins on the cell surface, which allow information transfer across the cell membrane. Super-resolution and single-molecule visualization of these proteins can be achieved by genetic…
View article: Control of G protein–coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains
Control of G protein–coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains Open
G protein–coupled receptors (GPCRs) control intracellular signaling cascades via agonist-dependent coupling to intracellular transducers including heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. In addition to their critical…
View article: Deuteration as a General Strategy to Enhance Azobenzene‐Based Photopharmacology
Deuteration as a General Strategy to Enhance Azobenzene‐Based Photopharmacology Open
Chemical photoswitches have become a widely used approach for the remote control of biological functions with spatiotemporal precision. Several molecular scaffolds have been implemented to improve photoswitch characteristics, ranging from …
View article: Deuteration as a General Strategy to Enhance Azobenzene‐Based Photopharmacology
Deuteration as a General Strategy to Enhance Azobenzene‐Based Photopharmacology Open
Chemical photoswitches have become a widely used approach for the remote control of biological functions with spatiotemporal precision. Several molecular scaffolds have been implemented to improve photoswitch characteristics, ranging from …
View article: A general method for near-infrared photoswitching in biology, demonstrated by the &gt;700 nm photocontrol of GPCR activity in brain slices
A general method for near-infrared photoswitching in biology, demonstrated by the >700 nm photocontrol of GPCR activity in brain slices Open
Azobenzene molecular switches are widely used to photocontrol material properties, and biological activity in cell culture, via photoisomerisation between E and Z isomers. However, because population photoswitching is incomplete, their dyn…
View article: Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia
Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia Open
Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enh…
View article: An epigenetic barrier sets the timing of human neuronal maturation
An epigenetic barrier sets the timing of human neuronal maturation Open
The pace of human brain development is highly protracted compared with most other species 1–7 . The maturation of cortical neurons is particularly slow, taking months to years to develop adult functions 3–5 . Remarkably, such protracted ti…
View article: Projection-Targeted Photopharmacology Reveals Distinct Anxiolytic Roles for Presynaptic mGluR2 in Prefrontal- and Insula-Amygdala Synapses
Projection-Targeted Photopharmacology Reveals Distinct Anxiolytic Roles for Presynaptic mGluR2 in Prefrontal- and Insula-Amygdala Synapses Open
Dissecting how membrane receptors regulate neural circuit function is critical for deciphering basic principles of neuromodulation and mechanisms of therapeutic drug action. Classical pharmacological and genetic approaches are not well-equ…
View article: Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk
Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk Open
Cellular signaling involves a large repertoire of membrane receptors operating in overlapping spatiotemporal regimes and targeting many common intracellular effectors. However, both the molecular mechanisms and the physiological roles of c…
View article: Distinct beta-arrestin coupling and intracellular trafficking of metabotropic glutamate receptor homo- and heterodimers
Distinct beta-arrestin coupling and intracellular trafficking of metabotropic glutamate receptor homo- and heterodimers Open
The metabotropic glutamate receptors (mGluRs) are family C, dimeric G protein–coupled receptors (GPCRs), which play critical roles in synaptic transmission. Despite an increasing appreciation of the molecular diversity of this family, how …
View article: A cholesterol switch controls phospholipid scrambling by G protein-coupled receptors
A cholesterol switch controls phospholipid scrambling by G protein-coupled receptors Open
Class A G protein-coupled receptors (GPCRs), a superfamily of cell membrane signaling receptors, moonlight as constitutively active phospholipid scramblases. The plasma membrane of metazoan cells is replete with GPCRs, yet has a strong res…
View article: Deuteration provides a general strategy to enhance azobenzene-based photopharmacology
Deuteration provides a general strategy to enhance azobenzene-based photopharmacology Open
Herein, we present deuterated azobenzene photoswitches as a general means of enhancing photopharmacological molecules. Deuteration can improve azobenzene performance in terms of light sensitivity, photoswitch efficiency, and photoswitch ki…
View article: Azobenzenes can achieve near-infrared photocontrol in biological systems, with quantitative Z→E photoisomerization, via singlet manifold photoredox
Azobenzenes can achieve near-infrared photocontrol in biological systems, with quantitative Z→E photoisomerization, via singlet manifold photoredox Open
Here we develop a high-performance approach to photoswitching, by exploiting singlet manifold photoredox between azobenzenes and covalently attached auxiliary chromophores. This enables well-penetrating red/NIR light of 630-740 nm, to whic…
View article: Synaptic plasticity via receptor tyrosine kinase/G protein-coupled receptor crosstalk
Synaptic plasticity via receptor tyrosine kinase/G protein-coupled receptor crosstalk Open
Summary Cellular signaling involves a large repertoire of membrane receptors operating in overlapping spatiotemporal regimes and targeting many common intracellular effectors. However, both the molecular mechanisms and physiological roles …
View article: Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains
Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains Open
G protein-coupled receptors (GPCRs) control intracellular signaling cascades via agonist-dependent coupling to intracellular transducers including heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. In addition to their critical…
View article: Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization
Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization Open
The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive …